bluuebunny/crossref_metadata_2025 huggingface dataset:
Distinct, ecotype-specific genome and proteome signatures in the marine cyanobacteria Prochlorococcus
Authors: Paul Sandip , Dutta Anirban , Bag Sumit K , Das Sabyasachi , Dutta Chitra
Published: February 2010

Background

The marine cyanobacteriumProchlorococcus marinus, having multiple ecotypes of distinct genotypic/phenotypic traits and being the first documented example of genome shrinkage in free-living organisms, offers an ideal system for studying niche-driven molecular micro-diversity in closely related microbes. The present study, through an extensive comparative analysis of various genomic/proteomic features of 6 high light (HL) and 6 low light (LL) adapted strains, makes an attempt to identify molecular determinants associated with their vertical niche partitioning.

Results

Pronounced strand-specific asymmetry in synonymous codon usage is observed exclusively in LL strains. Distinct dinucleotide abundance profiles are exhibited by 2 LL strains with larger genomes and G+C-content ≈ 50% (group LLa), 4 LL strains having reduced genomes and G+C-content ≈ 35-37% (group LLb), and 6 HL strains. Taking into account the emergence of LLa, LLb and HL strains (based on 16S rRNA phylogeny), a gradual increase in average aromaticity, pI values and beta- & coil-forming propensities and a decrease in mean hydrophobicity, instability indices and helix-forming propensities of core proteins are observed. Greater variations in orthologous gene repertoire are found between LLa and LLb strains, while higher number of positively selected genes exist between LL and HL strains.

Conclusion

Strains of differentProchlorococcusgroups are characterized by distinct compositional, physicochemical and structural traits that are not mere remnants of a continuous genetic drift, but are potential outcomes of a grand scheme of niche-oriented stepwise diversification, that might have driven them chronologically towards greater stability/fidelity and invoked upon them a special ability to inhabit diverse oceanic environments.
Reducing the haystack to find the needle: improved protein identification after fast elimination of non-interpretable peptide MS/MS spectra and noise reduction
Authors: Mujezinovic Nedim , Schneider Georg , Wildpaner Michael , Mechtler Karl , Eisenhaber Frank
Published: February 2010

Background

Tandem mass spectrometry (MS/MS) has become a standard method for identification of proteins extracted from biological samples but the huge number and the noise contamination of MS/MS spectra obstruct swift and reliable computer-aided interpretation. Typically, a minor fraction of the spectra per sample (most often, only a few %) and about 10% of the peaks per spectrum contribute to the final result if protein identification is not prevented by the noise at all.

Results

Two fast preprocessing screens can substantially reduce the haystack of MS/MS data. (1) Simple sequence ladder rules remove spectra non-interpretable in peptide sequences. (2) Modified Fourier-transform-based criteria clear background in the remaining data. In average, only a remainder of 35% of the MS/MS spectra (each reduced in size by about one quarter) has to be handed over to the interpretation software for reliable protein identification essentially without loss of information, with a trend to improved sequence coverage and with proportional decrease of computer resource consumption.

Conclusions

The search for sequence ladders in tandem MS/MS spectra with subsequent noise suppression is a promising strategy to reduce the number of MS/MS spectra from electro-spray instruments and to enhance the reliability of protein matches. Supplementary material and the software are available from an accompanying WWW-site with the URL http://mendel.bii.a-star.edu.sg/mass-spectrometry/MSCleaner-2.0/.
Bioinformatic search of plant microtubule-and cell cycle related serine-threonine protein kinases
Authors: Karpov Pavel A , Nadezhdina Elena S , Yemets Alla I , Matusov Vadym G , Nyporko Alexey Yu , Shashina Nadezhda Yu , Blume Yaroslav B
Published: February 2010

A bioinformatic search was carried for plant homologues of human serine-threonine protein kinases involved in regulation of cell division and microtubule protein phosphorylation (SLK, PAK6, PAK7, MARK1, MAST2, TTBK1, TTBK2, AURKA, PLK1, PLK4 and PASK). A number of SLK, MAST2 and AURKA plant homologues were identified. The closest identified homologue of human AURKA kinase was a protein of unknown function, A7PY12/GSVIVT00026259001 fromVitis vinifera(herein named as "STALK", Serine-Threonine Aurora-Like Kinase). Analysis of STALK's three-dimensional structure confirmed its relationship to the subgroup of AURKA-like protein kinases.
Data integration and exploration for the identification of molecular mechanisms in tumor-immune cells interaction
Authors: Mlecnik Bernhard , Sanchez-Cabo Fatima , Charoentong Pornpimol , Bindea Gabriela , Pagès Franck , Berger Anne , Galon Jerome , Trajanoski Zlatko
Published: February 2010

Cancer progression is a complex process involving host-tumor interactions by multiple molecular and cellular factors of the tumor microenvironment. Tumor cells that challenge immune activity may be vulnerable to immune destruction. To address this question we have directed major efforts towards data integration and developed and installed a database for cancer immunology with more than 1700 patients and associated clinical data and biomolecular data. Mining of the database revealed novel insights into the molecular mechanisms of tumor-immune cell interaction. In this paper we present the computational tools used to analyze integrated clinical and biomolecular data. Specifically, we describe a database for heterogenous data types, the interfacing bioinformatics and statistical tools including clustering methods, survival analysis, as well as visualization methods. Additionally, we discuss generic issues relevant to the integration of clinical and biomolecular data, as well as recent developments in integrative data analyses including biomolecular network reconstruction and mathematical modeling.
Bimodal gene expression patterns in breast cancer
Authors: Bessarabova Marina , Kirillov Eugene , Shi Weiwei , Bugrim Andrej , Nikolsky Yuri , Nikolskaya Tatiana
Published: February 2010

We identified a set of genes with an unexpected bimodal distribution among breast cancer patients in multiple studies. The property of bimodality seems to be common, as these genes were found on multiple microarray platforms and in studies with different end-points and patient cohorts. Bimodal genes tend to cluster into small groups of four to six genes with synchronised expression within the group (but not between the groups), which makes them good candidates for robust conditional descriptors. The groups tend to form concise network modules underlying their function in cancerogenesis of breast neoplasms.
Complex sense-antisense architecture of TNFAIP1/POLDIP2 on 17q11.2 represents a novel transcriptional structural-functional gene module involved in breast cancer progression
Authors: Grinchuk Oleg V , Motakis Efthimios , Kuznetsov Vladimir A
Published: February 2010

Background

A sense-antisense gene pair (SAGP) is a gene pair where two oppositely transcribed genes share a common nucleotide sequence region. In eukaryotic genomes, SAGPs can be organized in complex sense-antisense architectures (CSAGAs) in which at least one sense gene shares loci with two or more antisense partners. As shown in several case studies, SAGPs may be involved in cancers, neurological diseases and complex syndromes. However, CSAGAs have not yet been characterized in the context of human disease or cancer.

Results

We characterize five genes (TMEM97, IFT20, TNFAIP1, POLDIP2 and TMEM199) organized in a CSAGA on 17q11.2 (we term this the TNFAIP1/POLDIP2 CSAGA) and demonstrate their strong and reproducible co-regulatory transcription pattern in breast cancer tumours. Genes of the TNFAIP1/POLDIP2 CSAGA are located inside the smallest region of recurrent amplification on 17q11.2 and their expression profile correlates with the DNA copy number of the region. Survival analysis of a group of 410 breast cancer patients revealed significant survival-associated individual genes and gene pairs in the TNFAIP1/POLDIP2 CSAGA. Moreover, several of the gene pairs associated with survival, demonstrated synergistic effects. Expression of genes-members of the TNFAIP1/POLDIP2 CSAGA also strongly correlated with expression of genes of ERBB2 core region of recurrent amplification on 17q12. We clearly demonstrate that the observed co-regulatory transcription profile of the TNFAIP1/POLDIP2 CSAGA is maintained not only by a DNA amplification mechanism, but also by chromatin remodelling and local transcription activation.

Conclusion

We have identified a novel TNFAIP1/POLDIP2 CSAGA and characterized its co-regulatory transcription profile in cancerous breast tissues. We suggest that the TNFAIP1/POLDIP2 CSAGA represents a clinically significant transcriptional structural-functional gene module associated with amplification of the genomic region on 17q11.2 and correlated with expression ERBB2 amplicon core genes in breast cancer. Co-expression pattern of this module correlates with histological grades and a poor prognosis in breast cancer when over-expressed. TNFAIP1/POLDIP2 CSAGA maps the risks of breast cancer relapse onto the complex genomic locus on 17q11.2.
The cell envelope subtilisin-like proteinase is a virulence determinant for Streptococcus suis
Authors: Bonifait Laetitia , de la Cruz Dominguez-Punaro Maria , Vaillancourt Katy , Bart Christian , Slater Josh , Frenette Michel , Gottschalk Marcelo , Grenier Daniel
Published: February 2010

Background

Streptococcus suisis a major swine pathogen and zoonotic agent that mainly causes septicemia, meningitis, and endocarditis. It has recently been suggested that proteinases produced byS. suis(serotype 2) are potential virulence determinants. In the present study, we screened aS. suismutant library created by the insertion of Tn917transposon in order to isolate a mutant deficient in a cell surface proteinase. We characterized the gene and assessed the proteinase for its potential as a virulence factor.

Results

Two mutants (G6G and M3G) possessing a single Tn917insertion were isolated. The affected gene coded for a protein (SSU0757) that shared a high degree of identity withStreptococccus thermophilusPrtS (95.9%) and, to a lesser extent, withStreptococcus agalactiaeCspA (49.5%), which are cell surface serine proteinases. The SSU0757 protein had a calculated molecular mass of 169.6 kDa and contained the catalytic triad characteristic of subtilisin family proteinases: motif I (Asp200), motif II (His239), and motif III (Ser568). SSU0757 also had the Gram-positive cell wall anchoring motif (Leu-Pro-X-Thr-Gly) at the carboxy-terminus, which was followed by a hydrophobic domain. All theS. suisisolates tested, which belonged to different serotypes, possessed the gene encoding the SSU0757 protein. The two mutants devoid of subtilisin-like proteinase activity had longer generation times and were more susceptible to killing by whole blood than the wild-type parent strain P1/7. The virulence of the G6G and M3G mutants was compared to the wild-type strain in the CD1 mouse model. Significant differences in mortality rates were noted between the P1/7 group and the M3G and G6G groups (p< 0.001).

Conclusion

In summary, we identified a gene coding for a cell surface subtilisin-like serine proteinase that is widely distributed inS. suis. Evidences were brought for the involvement of this proteinase inS. suisvirulence.
Cellular processes of v-Src transformation revealed by gene profiling of primary cells - Implications for human cancer
Authors: Maślikowski Bart M , Néel Benjamin D , Wu Ying , Wang Lizhen , Rodrigues Natalie A , Gillet Germain , Bédard Pierre-André
Published: February 2010

Background

Cell transformation by the Src tyrosine kinase is characterized by extensive changes in gene expression. In this study, we took advantage of several strains of the Rous sarcoma virus (RSV) to characterize the patterns of v-Src-dependent gene expression in two different primary cell types, namely chicken embryo fibroblasts (CEF) and chicken neuroretinal (CNR) cells. We identified a common set of v-Src regulated genes and assessed if their expression is associated with disease-free survival using several independent human tumor data sets.

Methods

CEF and CNR cells were infected with transforming, non-transforming, and temperature sensitive mutants of RSV to identify the patterns of gene expression in response to v-Src-transformation. Microarray analysis was used to measure changes in gene expression and to define a common set of v-Src regulated genes (CSR genes) in CEF and CNR cells. A clustering enrichment regime using the CSR genes and two independent breast tumor data-sets was used to identify a 42-gene aggressive tumor gene signature. The aggressive gene signature was tested for its prognostic value by conducting survival analyses on six additional tumor data sets.

Results

The analysis of CEF and CNR cells revealed that cell transformation by v-Src alters the expression of 6% of the protein coding genes of the genome. A common set of 175 v-Src regulated genes (CSR genes) was regulated in both CEF and CNR cells. Within the CSR gene set, a group of 42 v-Src inducible genes was associated with reduced disease- and metastasis-free survival in several independent patient cohorts with breast or lung cancer. Gene classes represented within this group include DNA replication, cell cycle, the DNA damage and stress responses, and blood vessel morphogenesis.

Conclusion

By studying the v-Src-dependent changes in gene expression in two types of primary cells, we identified a set of 42 inducible genes associated with poor prognosis in breast and lung cancer. The identification of these genes provides a set of biomarkers of aggressive tumor behavior and a framework for the study of cancer cells characterized by elevated Src kinase activity.
Incidence of oral cancer in relation to nickel and arsenic concentrations in farm soils of patients' residential areas in Taiwan
Authors: Su Che-Chun , Lin Yo-Yu , Chang Tsun-Kuo , Chiang Chi-Ting , Chung Jian-An , Hsu Yun-Ying , Lian Ie-Bin
Published: February 2010

Background

To explore if exposures to specific heavy metals in the environment is a new risk factor of oral cancer, one of the fastest growing malignancies in Taiwan, in addition to the two established risk factors, cigarette smoking and betel quid chewing.

Methods

This is an observational study utilized the age-standardized incidence rates of oral cancer in the 316 townships and precincts of Taiwan, local prevalence rates of cigarette smoking and betel quid chewing, demographic factors, socio-economic conditions, and concentrations in farm soils of the eight kinds of heavy metal. Spatial regression and GIS (Geographic Information System) were used. The registration contained 22,083 patients, who were diagnosed with oral cancer between 1982 and 2002. The concentrations of metal in the soils were retrieved from a nation-wide survey in the 1980s.

Results

The incidence rate of oral cancer is geographically related to the concentrations of arsenic and nickel in the patients' residential areas, with the prevalence of cigarette smoking and betel quid chewing as controlled variables.

Conclusions

Beside the two established risk factors, cigarette smoking and betel quid chewing, arsenic and nickel in farm soils may be new risk factors for oral cancer. These two kinds of metal may involve in the development of oral cancer. Further studies are required to understand the pathways via which metal in the farm soils exerts its effects on human health.
High-throughput detection of mutations responsible for childhood hearing loss using resequencing microarrays
Authors: Kothiyal Prachi , Cox Stephanie , Ebert Jonathan , Husami Ammar , Kenna Margaret A , Greinwald John H , Aronow Bruce J , Rehm Heidi L
Published: February 2010

Background

Despite current knowledge of mutations in 45 genes that can cause nonsyndromic sensorineural hearing loss (SNHL), no unified clinical test has been developed that can comprehensively detect mutations in multiple genes. We therefore designed Affymetrix resequencing microarrays capable of resequencing 13 genes mutated in SNHL (GJB2, GJB6, CDH23, KCNE1, KCNQ1, MYO7A, OTOF, PDS, MYO6, SLC26A5, TMIE, TMPRSS3, USH1C). We present results from hearing loss arrays developed in two different research facilities and highlight some of the approaches we adopted to enhance the applicability of resequencing arrays in a clinical setting.

Results

We leveraged sequence and intensity pattern features responsible for diminished coverage and accuracy and developed a novel algorithm, sPROFILER, which resolved >80% of no-calls from GSEQ and allowed 99.6% (range: 99.2-99.8%) of sequence to be called, while maintaining overall accuracy at >99.8% based upon dideoxy sequencing comparison.

Conclusions

Together, these findings provide insight into critical issues for disease-centered resequencing protocols suitable for clinical application and support the use of array-based resequencing technology as a valuable molecular diagnostic tool for pediatric SNHL and other genetic diseases with substantial genetic heterogeneity.
Suppressive and additive effects in protection mediated by combinations of monoclonal antibodies specific for merozoite surface protein 1 of Plasmodium yoelii
Authors: Eslava Irosoki , Payares Gilberto , Pernia Beatriz M , Holder Anthony A , Spencer Lilian M
Published: February 2010

Background

The merozoite surface protein (MSP)-1 is a target antigen of protective immunity and a malaria vaccine candidate. The nature of this protective immune response warrants further investigation: although specific antibody is thought to play a major role, the mechanisms of protection are still unclear. Monoclonal antibodies (mAbs) specific for the C-terminus of MSP-1 fromPlasmodium yoeliihave been shown previously to provide protection against challenge infection when administered by passive immunization to mice. Three protective mAbs were re-examined and, in particular, the effect of combinations of antibodies on the protection provided was studied. It was found that a combination of two antibodies can either provide additive protective effects or result in a suppression of protection. In this report the importance of antibody subclass and epitope specificity in the outcome of these passive immunization experiments are discussed.

Methods

The minimum protective dose (MPD) for each mAb was determined, and then combinations of antibody at their MPD were investigated for their ability to control parasitaemia and promote survival in groups of mice. Mice were inoculated over three days with the MPD and challenged with a blood stage infection of the virulentP. yoelii17 XL. The resultant parasitaemia was assessed daily on Giemsa-stained blood films. Following the infection the presence of MSP-1 specific antibodies in the sera was monitored, and the proliferative responses of cells in the spleen of protected mice were measured.

Results

Combining antibodies resulted in either an additive effect on protection, with reduced peak parasitaemia and better survival, or resulted in a suppression of protection over that achieved by a single antibody alone. An additive effect was observed when B6 and F5 that have the same isotype and similar fine specificity, were combined. However, a combination of mAb D3, an IgG2a, with either B6 or F5 (both IgG3) suppressed protection, an effect that may have been due to the combination of different isotypes or to the different fine specificity of the antibodies.

Conclusions

These results suggest that a combination of protective antibodies with either the same or different isotypes can produce either an additive or a suppressive effect in passive immunization. This phenomenon may be important in better understanding immunity in this experimental mouse model of malaria.
Quality of care and health-related quality of life of climacteric stage women cared for in family medicine clinics in Mexico
Authors: Doubova Dubova Svetlana Vladislavovna , Flores-Hernández Sergio , Rodriguez-Aguilar Leticia , Pérez-Cuevas Ricardo
Published: February 2010

Objectives

1) To design and validate indicators to measure the quality of the process of care that climacteric stage women receive in family medicine clinics (FMC). 2) To assess the quality of care that climacteric stage women receive in FMC. 3) To determine the association between quality of care and health-related quality of life (HR-QoL) among climacteric stage women.

Methods

The study had two phases: I. Design and validation of indicators to measure the quality of care process by using the RAND/UCLA Appropriateness Method. II. Evaluation of the quality of care and its association with HR-QoL through a cross-sectional study conducted in two FMC located in Mexico City that included 410 climacteric stage women. The quality of care was measured by estimating the percentage of recommended care received (PRCR) by climacteric stage women in three process components: health promotion, screening, and treatment. The HR-QoL was measured using the Cervantes scale (0-155). The association between quality of care and HR-QoL was estimated through multiple linear regression analysis.

Results

The lowest mean of PRCR was for the health promotion component (24.1%) and the highest for the treatment component (86.6%). The mean of HR-QoL was 50.1 points. The regression analysis showed that in the treatment component, for every 10 additional points of the PRCR, the global HR-QoL improved 2.8 points on the Cervantes scale (coefficient -0.28, P < 0.0001).

Conclusion

The indicators to measure quality of care for climacteric stage women are applicable and feasible in family medicine settings. There is a positive association between the quality of the treatment component and HR-QoL; this would encourage interventions to improve quality of care for climacteric stage women.
Comparison of three rapamycin dosing schedules in A/J Tsc2+/- mice and improved survival with angiogenesis inhibitor or asparaginase treatment in mice with subcutaneous tuberous sclerosis related tumors
Authors: Woodrum Chelsey , Nobil Alison , Dabora Sandra L
Published: February 2010

Background

Tuberous Sclerosis Complex (TSC) is an autosomal dominant tumor disorder characterized by the growth of hamartomas in various organs including the kidney, brain, skin, lungs, and heart. Rapamycin has been shown to reduce the size of kidney angiomyolipomas associated with TSC; however, tumor regression is incomplete and kidney angiomyolipomas regrow after cessation of treatment. Mouse models of TSC2 related tumors are useful for evaluating new approaches to drug therapy for TSC.

Methods

In cohorts of Tsc2
+/- mice, we compared kidney cystadenoma severity in A/J and C57BL/6 mouse strains at both 9 and 12 months of age. We also investigated age related kidney tumor progression and compared three different rapamycin treatment schedules in cohorts of A/J Tsc2
+/- mice. In addition, we used nude mice bearing Tsc2
-/- subcutaneous tumors to evaluate the therapeutic utility of sunitinib, bevacizumab, vincristine, and asparaginase.

Results

TSC related kidney disease severity is 5-10 fold higher in A/J Tsc2
+/- mice compared with C57BL/6 Tsc2
+/- mice. Similar to kidney angiomyolipomas associated with TSC, the severity of kidney cystadenomas increases with age in A/J Tsc2
+/- mice. When rapamycin dosing schedules were compared in A/J Tsc2
+/- cohorts, we observed a 66% reduction in kidney tumor burden in mice treated daily for 4 weeks, an 82% reduction in mice treated daily for 4 weeks followed by weekly for 8 weeks, and an 81% reduction in mice treated weekly for 12 weeks. In the Tsc2
-/- subcutaneous tumor mouse model, vincristine is not effective, but angiogenesis inhibitors (sunitinib and bevacizumab) and asparaginase are effective as single agents. However, these drugs are not as effective as rapamycin in that they increased median survival only by 24-27%, while rapamycin increased median survival by 173%.

Conclusions

Our results indicate that the A/J Tsc2
+/- mouse model is an improved, higher through-put mouse model for future TSC preclinical studies. The rapamycin dosing comparison study indicates that the duration of rapamycin treatment is more important than dose intensity. We also found that angiogenesis inhibitors and asparaginase reduce tumor growth in a TSC2 tumor mouse model and although these drugs are not as effective as rapamycin, these drug classes may have some therapeutic potential in the treatment of TSC related tumors.
A metabolic signature of long life in Caenorhabditis elegans
Authors: Fuchs Silke , Bundy Jacob G , Davies Sarah K , Viney Jonathan M , Swire Jonathan S , Leroi Armand M
Published: February 2010

Background

Many Caenorhabditis elegans mutations increase longevity and much evidence suggests that they do so at least partly via changes in metabolism. However, up until now there has been no systematic investigation of how the metabolic networks of long-lived mutants differ from those of normal worms. Metabolomic technologies, that permit the analysis of many untargeted metabolites in parallel, now make this possible. Here we use one of these, 1H nuclear magnetic resonance spectroscopy, to investigate what makes long-lived worms metabolically distinctive.

Results

We examined three classes of long-lived worms: dauer larvae, adult Insulin/IGF-1 signalling (IIS)-defective mutants, and a translation-defective mutant. Surprisingly, these ostensibly different long-lived worms share a common metabolic signature, dominated by shifts in carbohydrate and amino acid metabolism. In addition the dauer larvae, uniquely, had elevated levels of modified amino acids (hydroxyproline and phosphoserine). We interrogated existing gene expression data in order to integrate functional (metabolite-level) changes with transcriptional changes at a pathway level.

Conclusions

The observed metabolic responses could be explained to a large degree by upregulation of gluconeogenesis and the glyoxylate shunt as well as changes in amino acid catabolism. These responses point to new possible mechanisms of longevity assurance in worms. The metabolic changes observed in dauer larvae can be explained by the existence of high levels of autophagy leading to recycling of cellular components.

See associated minireview: http://jbiol.com/content/9/1/7
Bilateral changes of TNF-α and IL-10 protein in the lumbar and cervical dorsal root ganglia following a unilateral chronic constriction injury of the sciatic nerve
Authors: Jančálek Radim , Dubový Petr , Svíženská Ivana , Klusáková Ilona
Published: February 2010

Background

There is a growing body of evidence that unilateral nerve injury induces bilateral response, the mechanism of which is not exactly known. Because cytokines act as crucial signaling molecules for response of peripheral nerves to injury, they may be induced to mediate the reaction in remote structures.

Methods

We studied levels of tumor necrosis factor α (TNF-α) and interleukin 10 (IL-10) proteins using ELISA in the ipsilateral and contralateral lumbar (L4-L5) and cervical (C7-C8) dorsal root ganglia (DRG) from naïve rats, rats operated on to create unilateral chronic constriction injury (CCI) of the sciatic nerve, and sham-operated rats. Withdrawal thresholds for mechanical allodynia and thermal hyperalgesia were measured in the ipsilateral and contralateral hind and forepaws.

Results

The ipsilateral hind paws of all rats operated upon for CCI displayed decreased withdrawal thresholds for mechanical allodynia and thermal hyperalgesia, while no significant behavioral changes were found in the contralateral hind paws and both forepaws. Significantly lower baseline levels of TNF-α and IL-10 protein were measured by ELISA in the lumbar than cervical DRG of naïve rats. Bilateral elevation of TNF-α was induced in both the lumbar and cervical DRG by unilateral CCI of the sciatic nerve for 7 and 14 days, while the level of IL-10 protein was increased bilaterally in the lumbar DRG 1 and 3 days after operation. IL-10 levels declined bilaterally even below baseline level in both cervical and lumbar DRG 7 days from CCI and normalized after 14 days. In contrast to no significant changes in TNF-α, level of IL-10 protein was significantly increased in the ipsilateral lumbar DRG after 3 days and bilaterally in the lumbar DRG after 14 days from sham operation.

Conclusions

The results of our experiments show a bilateral elevation of TNF-α and IL-10 not only in the homonymous DRG but also in the heteronymous DRG unassociated with the injured nerve. This suggests that bilaterally increased levels of TNF-α and IL-10 in DRG following unilateral CCI are linked with general neuroinflammatory reaction of the nervous system to injury rather than only to development and maintenance of neuropathic pain.
SARS coronavirus protein 7a interacts with human Ap4A-hydrolase
Authors: Vasilenko Natalia , Moshynskyy Igor , Zakhartchouk Alexander
Published: February 2010

The SARS coronavirus (SARS-CoV) open reading frame 7a (ORF 7a) encodes a 122 amino acid accessory protein. It has no significant sequence homology with any other known proteins. The 7a protein is present in the virus particle and has been shown to interact with several host proteins; thereby implicating it as being involved in several pathogenic processes including apoptosis, inhibition of cellular protein synthesis, and activation of p38 mitogen activated protein kinase. In this study we present data demonstrating that the SARS-CoV 7a protein interacts with human Ap4A-hydrolase (asymmetrical diadenosine tetraphosphate hydrolase, EC 3.6.1.17). Ap4A-hydrolase is responsible for metabolizing the "allarmone" nucleotide Ap4A and therefore likely involved in regulation of cell proliferation, DNA replication, RNA processing, apoptosis and DNA repair. The interaction between 7a and Ap4A-hydrolase was identified using yeast two-hybrid screening. The interaction was confirmed by co-immunoprecipitation from cultured human cells transiently expressing V5-His tagged 7a and HA tagged Ap4A-hydrolase. Human tissue culture cells transiently expressing 7a and Ap4A-hydrolase tagged with EGFP and Ds-Red2 respectively show these proteins co-localize in the cytoplasm.
Genome-wide methylation and expression profiling identifies promoter characteristics affecting demethylation-induced gene up-regulation in melanoma
Authors: Rubinstein Jill C , Tran Nam , Ma Shuangge , Halaban Ruth , Krauthammer Michael
Published: February 2010

Background

Abberant DNA methylation at CpG dinucleotides represents a common mechanism of transcriptional silencing in cancer. Since CpG methylation is a reversible event, tumor supressor genes that have undergone silencing through this mechanism represent promising targets for epigenetically active anti-cancer therapy. The cytosine analog 5-aza-2'-deoxycytidine (decitabine) induces genomic hypomethylation by inhibiting DNA methyltransferase, and is an example of an epigenetic agent that is thought to act by up-regulating silenced genes.

Methods

It is unclear why decitabine causes some silenced loci to re-express, while others remain inactive. By applying data-mining techniques to large-scale datasets, we attempted to elucidate the qualities of promoter regions that define susceptibility to the drug's action. Our experimental data, derived from melanoma cell strains, consist of genome-wide gene expression data before and after treatment with decitabine, as well as genome-wide data on un-treated promoter methylation status, and validation of specific genes by bisulfite sequencing.

Results

We show that the combination of promoter CpG content and methylation level informs the ability of decitabine treatment to up-regulate gene expression. Promoters with high methylation levels and intermediate CpG content appear most susceptible to up-regulation by decitabine, whereas few of those highly methylated promoters with high CpG content are up-regulated. For promoters with low methylation levels, those with high CpG content are more likely to be up-regulated, whereas those with low CpG content are underrepresented among up-regulated genes.

Conclusions

Clinically, elucidating the patterns of action of decitabine could aid in predicting the likelihood of up-regulating epigenetically silenced tumor suppressor genes and others from pathways involved with tumor biology. As a first step toward an eventual translational application, we build a classifier to predict gene up-regulation based on promoter methylation and CpG content, which achieves a performance of 0.77 AUC.
Plasma Adrenomedullin level in Egyptian children and Adolescents with type 1 diabetes mellitus: relationship to microvascular complications
Authors: El-Habashy Safinaz A , Matter Randa M , El-Hadidi Eman S , Afifi Hala R
Published: February 2010

Background

Adrenomedullin (AM) is known to be elevated in different clinical situations including diabetes mellitus (DM), but its potential role in the pathogenesis of vascular complications in diabetic children and adolescents is to be clarified. Hence, the study aimed at assessment of plasma adrenomedullin levels in children and adolescents with type 1 DM and correlation of these levels with metabolic control and diabetic microvascular complications (MVC).

Methods

The study was performed in the Diabetes Specialized Clinic, Children's Hospital of Ain Shams University in Cairo, Egypt. It included 55 diabetic children and adolescents (mean age 13.93 ± 3.15 years) who were subdivided into 40 with no MVC and 15 with MVC. Thirty healthy subjects, age-and sex- matched were included as control group (mean age 12.83 ± 2.82 years). Patients and controls were assessed for glycosylated hemoglobin (HbA1c) and plasma adrenomedullin assay using ELISA technique.

Results

Mean plasma AM levels were significantly increased in patients with and without MVC compared to control group, (110.6 pg/mL, 60.25 pg/mL and 39.2 pg/mL respectively) (P < 0.01) with higher levels in those with MVC (P < 0.05). Plasma AM levels were positively correlated with both duration of diabetes (ρ = 0.703, P < 0.001) and glycemic control (HbA1c) (ρ = 0.453, P < 0.001).

Conclusion

Higher plasma AM levels in diabetics particularly in those with MVC & its correlation with diabetes duration and metabolic control may reflect the role of AM in diabetic vasculopathy in the pediatric age group.
Protein tyrosine phosphatase SHP-1 positively regulates TLR-induced IL-12p40 production in macrophages through inhibition of phosphatidylinositol 3-kinase
Authors: Zhou Delu , Collins Cathleen A , Wu Ping , Brown Eric J
Published: February 2010

By regulating PI3K activity and IL-12b promoter nucleosome remodeling, protein tyrosine phosphatase SHP-1 controls IL-12p40 production in macrophages.

SHP-1 is a cytoplasm protein tyrosine phosphatase expressed primarily in hematopoietic cells. In the immune system, SHP-1 plays critical roles in regulation of many receptor-mediated signaling cascades, and SHP-1 deficiency in mice causes spontaneous inflammation and autoimmunity. Here, we report a unique requirement for SHP-1 in interleukin-12/23 p40 (IL-12p40) production in response to Toll-like receptor (TLR) stimulation in macrophages. Bone marrow-derived macrophages (BMDMs) lacking significant SHP-1 activity display a profound defect in IL-12p40 synthesis in response to lipopolysaccharide, peptidoglycan, and synthetic TLR ligands, while producing normal amounts of other proinflammatory cytokines, such as TNFα and IL-6. Inhibition of SHP-1 function in wild-type BMDMs decreases IL-12p40, and expression of functional SHP-1 protein in mutant cells restores IL-12p40 production following TLR ligation. SHP-1 regulation of IL-12p40 transcription requires both its catalytic activity and phosphotyrosine binding by its N-terminal SH2 domain and is mediated via repression of, and interaction with, phosphatidylinositol 3-kinase, without affecting c-Rel activation. In contrast to normal NF-κB activation, SHP-1-defective mev/mev macrophages display a defect in nucleosome remodeling at the IL-12p40 promoter, and phosphatidylinositol 3-kinase inhibition significantly restores normal nucleosome remodeling in mev/mev macrophages. Thus, there is a critical role for the tyrosine phosphatase activity of SHP-1 for induction of IL-12p40 production in macrophages in response to TLR ligands, a novel mechanism for host regulation of a specific proinflammatory cytokine important in both innate and adaptive immunity.
Heterogeneity in a mouse model of histiocytosis: transformation of Langerin+ dendritic cells, macrophages, and precursors
Authors: Leenen Pieter J M , Bechan Gitanjali I , Melis Marleen , den Broeder Berlinda J H , Löhler Jürgen , Egeler R Maarten
Published: February 2010

Mouse histiocytosis sarcoma virus infection induces a heterogeneous disease with characteristics of Mφ/DC neoplasms involving Langerin+ DC, Mφ, and precursors.

Neoplastic diseases of macrophages (Mφ) and dendritic cells (DC), collectively called histiocytoses, are relatively rare. The etiology of most forms of histiocytosis is poorly understood, and the development of animal models is crucial for further research in this field. Previously, an animal model for malignant histiocytosis (MH), involving transformed histiocytic cells, has been generated by infecting mice with malignant histiocytosis sarcoma virus (MHSV). However, increased insight into the heterogeneity of Mφ and DC, and the associated reappraisal of human proliferative diseases involving these cells inspired us to re-evaluate the mouse model. We analyzed spleen, bone marrow, and lymph nodes of susceptible mice at various time points after infection. From day 11 onwards, a heterogeneous population of cells, consisting of CD8α+ Langerin+ DC, ER-MP58+ CD11b+ myeloid precursor cells, CD169+ metallophilic Mφ, and CD71hi erythroblasts, was affected by viral transformation. In different mice, these subsets expanded at different rates in different organs, causing a variable disease profile in terminal stages. Cell lines, which were generated from MHSV-transformed tumors, showed a DC-like morphology and phenotype, and appeared to be arrested in different stages of maturation. Upon injection into healthy mice, different preferential homing patterns were observed for the various cell lines, and the cells acquired distinct phenotypes depending on the organ of homing. This indicates that these transformed cells adapt to their microenvironment by switching between precursor, DC/Langerhans cell, and Mφ phenotypes. Our results demonstrate that the MHSV model represents a heterogeneous neoplastic disease with characteristics of Mφ/DC sarcomas.
R. D. Collison Black, 1922–2008: A Personal Tribute
Authors: Winch Donald
Published: February 2010

Donald Winch is an emeritus professor at the University of Sussex.
The Problem of Passive Observation
Authors: Boumans Marcel
Published: February 2010

Trygve Haavelmo's methodological manifesto “The Probability Approach in Econometrics” not only laid down the paradigm for the research pursued at the Cowles Commission, but also sets out a strategy for measurement outside the laboratory. His conceptualization of “passive observation” is still very useful for understanding measurements where intervention is not possible.

Haavelmo's classic is very rich: it provided the framework for introducing probabilistic methods in econometrics and a profound discussion on invariance (autonomy). These subjects are well treated by various historians of econometrics. This does not, however, apply to the problem of passive observation. It is only mentioned, if it is mentioned at all, in relation to the discussion of autonomy, but that is it.

This essay will give a reconstruction of his discussion of “factual” and “potential” influences, which provided Haavelmo the framework to discuss “Nature's experiments” and will allow us to discuss measurement outside the laboratory more generally.
Interdependence, the Invisible Hand, and Equilibrium in Adam Smith
Authors: Witztum Amos
Published: February 2010

The question of whether there is general equilibrium in Adam Smith lies at the heart of the battlefield between those who wish to see Smith as a precursor of modern economics and those who see in his writing an alternative system. In this article I will argue that it is possible for general equilibrium to be present in Smith and yet, for his system to be an alternative to, rather than a precursor of, modern economics. I will show that coordination is crucial in both systems although the narratives that produce it are fundamentally different. I will argue that in the end, there are two coordinating mechanisms in Smith. First, there is the invisible hand of the Theory of Moral Sentiments, which facilitates the process of specialization and trade (or division of labor). It is a coordinating mechanism and not a tautology, as it is based on a presumption about human behavior yet it is not dependent on the market. Without the belief in the coordinating power of the invisible hand, labor would not have been divided and people would not have become dependent on others. Second, the growing dependency on strangers brings to the fore the coordinating powers of the market. Their function in this elaborate system is to uphold the promise of the invisible hand of the Theory of Moral Sentiments and guarantee life's necessities, as well as support the new social drive that, through the deception of nature, is manifested in the accumulation of wealth. I will argue that according to Smith, these functions are well performed by the markets when prices are all at their natural rate. It is only then that across all industries and employment, division of labor would occur, affluence would be generated, and the worse-off people in society would not be left behind. The mere existence of general equilibrium ensures none of the above and is hence unrelated to the question of successful coordination.
World Literature and the Dynamic Function of Translation
Authors: Ning Wang
Published: February 2010

Although the term world literature encompasses texts composed in multiple languages, translation makes possible a body of literature from many linguistic and cultural backgrounds that circulates in international critical discourse and is broadly recognized as world literature. Thus the category of world literature presupposes authors and translators driven to contribute to the canon of world literature. Walter Benjamin observes that translation endows a literary work with “continued life” or “afterlife,” without which many works of global significance remain “dead” or marginalized. Inspired by Benjamin's view of translation and by David Damrosch's emphasis on world literature as a distinctive type of literary production, this essay examines the issues that influence the potential of literary works to win acclaim in translation as world literature. Chinese literature provides a useful case study, since Chinese translators have been more focused historically on translating works into Chinese than on exporting Chinese literature into other languages and thus increasing its chances at an “afterlife.”
The Poetry of the Future; Or, Periodizing the Nineteenth Century
Authors: Parker Andrew
Published: February 2010

The question of poetry's future was asked with surprising frequency across various Western literary languages during the nineteenth century. In Walt Whitman's little-known essay “The Poetry of the Future” (1881), in Arthur Rimbaud's celebrated “Voyant” letter to Paul Demeny (1871), and in a famous passage near the beginning of Karl Marx's Eighteenth Brumaire of Louis Bonaparte (1851–52), a future poetry was greeted as an original poetry. In each of these instances, however, breaking with the past entailed imitating it, which suggests that poetry's future looks much like its past, the way forward indistinguishable from the way back.
Making a difference together: reciprocal interactions in C. elegans and zebrafish asymmetric neural development
Authors: Taylor Robert W. , Hsieh Yi-Wen , Gamse Joshua T. , Chuang Chiou-Fen
Published: February 2010

Brain asymmetries are thought to increase neural processing capacity and to prevent interhemispheric conflict. In order to develop asymmetrically, neurons must be specified along the left-right axis, assigned left-side versus right-side identities and differentiate appropriately. In C. elegans and zebrafish, the cellular and molecular mechanisms that lead to neural asymmetries have recently come to light. Here, we consider recent insights into the mechanisms involved in asymmetrical neural development in these two species. Although the molecular details are divergent, both organisms use iterative cell-cell communication to establish left-right neuronal identity.
Transcriptional control of stem cell maintenance in theDrosophilaintestine
Authors: Bardin Allison J. , Perdigoto Carolina N. , Southall Tony D. , Brand Andrea H. , Schweisguth François
Published: February 2010

Adult stem cells maintain tissue homeostasis by controlling the proper balance of stem cell self-renewal and differentiation. The adult midgut of Drosophila contains multipotent intestinal stem cells (ISCs) that self-renew and produce differentiated progeny. Control of ISC identity and maintenance is poorly understood. Here we find that transcriptional repression of Notch target genes by a Hairless-Suppressor of Hairless complex is required for ISC maintenance, and identify genes of the Enhancer of split complex [E(spl)-C] as the major targets of this repression. In addition, we find that the bHLH transcription factor Daughterless is essential to maintain ISC identity and that bHLH binding sites promote ISC-specific enhancer activity. We propose that Daughterless-dependent bHLH activity is important for the ISC fate and that E(spl)-C factors inhibit this activity to promote differentiation.
Signaling via Alk5 controls the ontogeny of lung Clara cells
Authors: Xing Yiming , Li Changgong , Li Aimin , Sridurongrit Somyoth , Tiozzo Caterina , Bellusci Saverio , Borok Zea , Kaartinen Vesa , Minoo Parviz
Published: February 2010

Clara cells, together with ciliated and pulmonary neuroendocrine cells, make up the epithelium of the bronchioles along the conducting airways. Clara cells are also known as progenitor or stem cells during lung regeneration after injury. The mechanisms of Clara cell differentiation are largely unknown. Transforming growth factor beta (TGFβ)is a multifunctional molecule with roles in normal development and disease pathogenesis. In this study, we deleted the TGFβ type I receptor Alk5 in the embryonic lung epithelium using Gata5-Cre mice. Absence of Alk5 blocked Clara cell differentiation but had no effect on ciliated or pulmonary neuroendocrine cells. Hairy/Enhancer of Split-1, which is expressed in Clara cell putative `progenitors' was found to be a downstream target of Alk5 in vivo and in vitro. Loss of Alk5-mediated signaling also stimulated Pten gene expression and inhibited ERK phosphorylation in vivo. Using lung epithelial cells, we show that Alk5-regulated Hes1 expression is stimulated through Pten and the MEK/ERK and PI3K/AKT pathways. Thus, the signaling pathway by which TGFβ/ALK5 regulates Clara cell differentiation may entail inhibition of Pten expression, which in turn activates ERK and AKT phosphorylation.