bluuebunny/crossref_metadata_2025 huggingface dataset:
The diversity and evolution of chelicerate hemocyanins
Authors: Rehm Peter , Pick Christian , Borner Janus , Markl Jürgen , Burmester Thorsten
Published: February 2012

Background

Oxygen transport in the hemolymph of many arthropod species is facilitated by large copper-proteins referred to as hemocyanins. Arthropod hemocyanins are hexamers or oligomers of hexamers, which are characterized by a high O2 transport capacity and a high cooperativity, thereby enhancing O2 supply. Hemocyanin subunit sequences had been available from horseshoe crabs (Xiphosura) and various spiders (Araneae), but not from any other chelicerate taxon. To trace the evolution of hemocyanins and the emergence of the large hemocyanin oligomers, hemocyanin cDNA sequences were obtained from representatives of selected chelicerate classes.

Results

Hemocyanin subunits from a sea spider, a scorpion, a whip scorpion and a whip spider were sequenced. Hemocyanin has been lost in Opiliones, Pseudoscorpiones, Solifugae and Acari, which may be explained by the evolution of trachea (i.e., taxon Apulmonata). Bayesian phylogenetic analysis was used to reconstruct the evolution of hemocyanin subunits and a relaxed molecular clock approach was applied to date the major events. While the sea spider has a simple hexameric hemocyanin, four distinct subunit types evolved before Xiphosura and Arachnida diverged around 470 Ma ago, suggesting the existence of a 4 × 6mer at that time. Subsequently, independent gene duplication events gave rise to the other distinct subunits in each of the 8 × 6mer hemocyanin of Xiphosura and the 4 × 6mer of Arachnida. The hemocyanin sequences were used to infer the evolutionary history of chelicerates. The phylogenetic trees support a basal position of Pycnogonida, a sister group relationship of Xiphosura and Arachnida, and a sister group relationship of the whip scorpions and the whip spiders.

Conclusion

Formation of a complex hemocyanin oligomer commenced early in the evolution of euchelicerates. A 4 × 6mer hemocyanin consisting of seven subunit types is conserved in most arachnids since more than 400 Ma, although some entelegyne spiders display selective subunit loss and independent oligomerization. Hemocyanins also turned out to be a good marker to trace chelicerate evolution, which is, however, limited by the loss of hemocyanin in some taxa. The molecular clock calculations were in excellent agreement with the fossil record, also demonstrating the applicability of hemocyanins for such approach.
Orthologous genes identified by transcriptome sequencing in the spider genus Stegodyphus
Authors: Mattila Tiina M , Bechsgaard Jesper S , Hansen Troels T , Schierup Mikkel H , Bilde Trine
Published: February 2012

Background

The evolution of sociality in spiders involves a transition from an outcrossing to a highly inbreeding mating system, a shift to a female biased sex ratio, and an increase in the reproductive skew among individuals. Taken together, these features are expected to result in a strong reduction in the effective population size. Such a decline in effective population size is expected to affect population genetic and molecular evolutionary processes, resulting in reduced genetic diversity and relaxed selective constraint across the genome. In the genus Stegodyphus, permanent sociality and regular inbreeding has evolved independently three times from periodic-social (outcrossing) ancestors. This genus is therefore an ideal model for comparative studies of the molecular evolutionary and population genetic consequences of the transition to a regularly inbreeding mating system. However, no genetic resources are available for this genus.

Results

We present the analysis of high throughput transcriptome sequencing of three Stegodyphus species. Two of these are periodic-social (Stegodyphus lineatus and S.tentoriicola) and one is permanently social (S. mimosarum). From non-normalized cDNA libraries, we obtained on average 7,000 putative uni-genes for each species. Three-way orthology, as predicted from reciprocal BLAST, identified 1,792 genes that could be used for cross-species comparison. Open reading frames (ORFs) could be deduced from 1,345 of the three-way alignments. Preliminary molecular analyses suggest a five- to ten-fold reduction in heterozygosity in the social S. mimosarum compared with the periodic-social species. Furthermore, an increased ratio of non-synonymous to synonymous polymorphisms in the social species indicated relaxed efficiency of selection. However, there was no sign of relaxed selection on the phylogenetic branch leading to S. mimosarum.

Conclusions

The 1,792 three-way ortholog genes identified in this study provide a unique resource for comparative studies of the eco-genomics, population genetics and molecular evolution of repeated evolution of inbreeding sociality within the Stegodyphus genus. Preliminary analyses support theoretical expectations of depleted heterozygosity and relaxed selection in the social inbreeding species. Relaxed selection could not be detected in the S. mimosarum lineage, suggesting that there has been a recent transition to sociality in this species.
Reference genome-independent assessment of mutation density using restriction enzyme-phased sequencing
Authors: Monson-Miller Jennifer , Sanchez-Mendez Diana C , Fass Joseph , Henry Isabelle M , Tai Thomas H , Comai Luca
Published: February 2012

Background

The availability of low cost sequencing has spurred its application to discovery and typing of variation, including variation induced by mutagenesis. Mutation discovery is challenging as it requires a substantial amount of sequencing and analysis to detect very rare changes and distinguish them from noise. Also challenging are the cases when the organism of interest has not been sequenced or is highly divergent from the reference.

Results

We describe the development of a simple method for reduced representation sequencing. Input DNA was digested with a single restriction enzyme and ligated to Y adapters modified to contain a sequence barcode and to provide a compatible overhang for ligation. We demonstrated the efficiency of this method at SNP discovery using rice and arabidopsis. To test its suitability for the discovery of very rare SNP, one control and three mutagenized rice individuals (1, 5 and 10 mM sodium azide) were used to prepare genomic libraries for Illumina sequencers by ligating barcoded adapters to NlaIII restriction sites. For genome-dependent discovery 15-30 million of 80 base reads per individual were aligned to the reference sequence achieving individual sequencing coverage from 7 to 15×. We identified high-confidence base changes by comparing sequences across individuals and identified instances consistent with mutations, i.e. changes that were found in a single treated individual and were solely GC to AT transitions. For genome-independent discovery 70-mers were extracted from the sequence of the control individual and single-copy sequence was identified by comparing the 70-mers across samples to evaluate copy number and variation. This de novo "genome" was used to align the reads and identify mutations as above. Covering approximately 1/5 of the 380 Mb genome of rice we detected mutation densities ranging from 0.6 to 4 per Mb of diploid DNA depending on the mutagenic treatment.

Conclusions

The combination of a simple and cost-effective library construction method, with Illumina sequencing, and the use of a bioinformatic pipeline allows practical SNP discovery regardless of whether a genomic reference is available.
The tyrosyl-tRNA synthetase like gene located in the tyramine biosynthesis cluster of Enterococcus duransis transcriptionally regulated by tyrosine concentration and extracellular pH
Authors: Linares Daniel M , Fernández Maria , Del-Río Beatriz , Ladero Victor , Martin Maria Cruz , Alvarez Miguel A
Published: February 2012

Background

The tyramine producer Enterococcus durans IPLA655 contains all the necessary genes for tyramine biosynthesis, grouped in the TDC cluster. This cluster includes tyrS, an aminoacyl-tRNA synthetase like gene.

Results

This work shows that tyrS was maximally transcribed in absence of tyrosine at acidic pH, showing a greater than 10-fold induction in mRNA levels over levels occurring in presence of tyrosine. Mapping of the tyrS transcriptional start site revealed an unusually long untranslated leader region of 322 bp, which displays the typical features of the T box transcriptional attenuation mechanism. The tyrosine concentration regulation of tyrS was found to be mediated by a transcription antitermination system, whereas the specific induction at acidic pH was regulated at transcription initiation level.

Conclusions

The expression of the tyrS gene present in the TDC cluster of E. durans is transcriptionally regulated by tyrosine concentration and extracelular pH. The regulation is mediated by both an antitermination system and the promoter itself.
Comparative transcriptome analysis of stylar canal cells identifies novel candidate genes implicated in the self-incompatibility response of Citrus clementina
Authors: Caruso Marco , Merelo Paz , Distefano Gaetano , La Malfa Stefano , Lo Piero Angela Roberta , Tadeo Francisco R , Talon Manuel , Gentile Alessandra
Published: February 2012

Background

Reproductive biology in citrus is still poorly understood. Although in recent years several efforts have been made to study pollen-pistil interaction and self-incompatibility, little information is available about the molecular mechanisms regulating these processes. Here we report the identification of candidate genes involved in pollen-pistil interaction and self-incompatibility in clementine (Citrus clementina Hort. ex Tan.). These genes have been identified comparing the transcriptomes of laser-microdissected stylar canal cells (SCC) isolated from two genotypes differing for self-incompatibility response ('Comune', a self-incompatible cultivar and 'Monreal', a self- compatible mutation of 'Comune').

Results

The transcriptome profiling of SCC indicated that the differential regulation of few specific, mostly uncharacterized transcripts is associated with the breakdown of self-incompatibility in 'Monreal'. Among them, a novel F-box gene showed a drastic up-regulation both in laser microdissected stylar canal cells and in self-pollinated whole styles with stigmas of 'Comune' in concomitance with the arrest of pollen tube growth. Moreover, we identify a non-characterized gene family as closely associated to the self-incompatibility genetic program activated in 'Comune'. Three different aspartic-acid rich (Asp-rich) protein genes, located in tandem in the clementine genome, were over-represented in the transcriptome of 'Comune'. These genes are tightly linked to a DELLA gene, previously found to be up-regulated in the self-incompatible genotype during pollen-pistil interaction.

Conclusion

The highly specific transcriptome survey of the stylar canal cells identified novel genes which have not been previously associated with self-pollen rejection in citrus and in other plant species. Bioinformatic and transcriptional analyses suggested that the mutation leading to self-compatibility in 'Monreal' affected the expression of non-homologous genes located in a restricted genome region. Also, we hypothesize that the Asp-rich protein genes may act as Ca2+ "entrapping" proteins, potentially regulating Ca2+ homeostasis during self-pollen recognition.
The HR2 polymorphism N140I in the HIV-1 gp41 combined with the HR1 V38A mutation is associated with a less cytopathic phenotype
Authors: Cunyat Francesc , Marfil Silvia , García Elisabet , Svicher Valentina , Pérez-Alvárez Nuria , Curriu Marta , Perno Carlo Federico , Clotet Bonaventura , Blanco Julià , Cabrera Cecilia
Published: February 2012

Background

Resistance to the fusion inhibitor enfuvirtide (ENF) is achieved by changes in the gp41 subunit of the HIV envelope glycoprotein (Env). Specific ENF-associated mutational pathways correlate with immunological recovery, even after virological failure, suggesting that the acquisition of ENF resistance alters gp41 pathogenicity. To test this hypothesis, we have characterized the expression, fusion capability, induction of CD4+T cell loss and single CD4+T cell death of 48 gp41 proteins derived from three patients displaying different amino acids (N, T or I) at position 140 that developed a V38A mutation after ENF-based treatment.

Results

In all cases, intra-patient comparison of Env isolated pre- or post-treatment showed comparable values of expression and fusogenic capacity. Furthermore, Env with either N or T at position 140 induced comparable losses of CD4+T-cells, irrespective of the residue present at position 38. Conversely, Env acquiring the V38A mutation in a 140I background induced a significantly reduced loss of CD4+T cells and lower single-cell death than did their baseline controls. No altered ability to induce single-cell death was observed in the other clones.

Conclusions

Overall, primary gp41 proteins with both V38A and N140I changes showed a reduced ability to induce single cell death and deplete CD4+T cells, despite maintaining fusion activity. The specificity of this phenotype highlights the relevance of the genetic context to the cytopathic capacity of Env and the role of ENF-resistance mutations in modulating viral pathogenicityin vivo, further supporting the hypothesis that gp41 is a critical mediator of HIV pathogenesis.
Genome skimming identifies polymorphism in tern populations and species
Authors: Jackson David George , Emslie Steven D , van Tuinen Marcel
Published: February 2012

Background

Terns (Charadriiformes: Sterninae) are a lineage of cosmopolitan shorebirds with a disputed evolutionary history that comprises several species of conservation concern. As a non-model system in genetics, previous study has left most of the nuclear genome unexplored, and population-level studies are limited to only 15% of the world's species of terns and noddies. Screening of polymorphic nuclear sequence markers is needed to enhance genetic resolution because of supposed low mitochondrial mutation rate, documentation of nuclear insertion of hypervariable mitochondrial regions, and limited success of microsatellite enrichment in terns. Here, we investigated the phylogenetic and population genetic utility for terns and relatives of a variety of nuclear markers previously developed for other birds and spanning the nuclear genome. Markers displaying a variety of mutation rates from both the nuclear and mitochondrial genome were tested and prioritized according to optimal cross-species amplification and extent of genetic polymorphism between (1) the main tern clades and (2) individual Royal Terns (Thalasseus maxima) breeding on the US East Coast.

Results

Results from this genome skimming effort yielded four new nuclear sequence-based markers for tern phylogenetics and 11 intra-specific polymorphic markers. Further, comparison between the two genomes indicated a phylogenetic conflict at the base of terns, involving the inclusion (mitochondrial) or exclusion (nuclear) of the Angel Tern (Gygis alba). Although limited mitochondrial variation was confirmed, both nuclear markers and a short tandem repeat in the mitochondrial control region indicated the presence of considerable genetic variation in Royal Terns at a regional scale.

Conclusions

These data document the value of intronic markers to the study of terns and allies. We expect that these and additional markers attained through next-generation sequencing methods will accurately map the genetic origin and species history of this group of birds.
The health informatics cohort enhancement project (HICE): using routinely collected primary care data to identify people with a lifetime diagnosis of psychotic disorder
Authors: Economou Alexis , Grey Michelle , McGregor Joanna , Craddock Nick , Lyons Ronan A , Owen Michael J , Price Vaughn , Thomson Sue , Walters James TR , Lloyd Keith
Published: February 2012

Background

We have previously demonstrated that routinely collected primary care data can be used to identify potential participants for trials in depression [1]. Here we demonstrate how patients with psychotic disorders can be identified from primary care records for potential inclusion in a cohort study. We discuss the strengths and limitations of this approach; assess its potential value and report challenges encountered.

Methods

We designed an algorithm with which we searched for patients with a lifetime diagnosis of psychotic disorders within the Secure Anonymised Information Linkage (SAIL) database of routinely collected health data. The algorithm was validated against the "gold standard" of a well established operational criteria checklist for psychotic and affective illness (OPCRIT). Case notes of 100 patients from a community mental health team (CMHT) in Swansea were studied of whom 80 had matched GP records.

Results

The algorithm had favourable test characteristics, with a very good ability to detect patients with psychotic disorders (sensitivity > 0.7) and an excellent ability not to falsely identify patients with psychotic disorders (specificity > 0.9).

Conclusions

With certain limitations our algorithm can be used to search the general practice data and reliably identify patients with psychotic disorders. This may be useful in identifying candidates for potential inclusion in cohort studies.
Computational analysis of pathogen-borne metallo β-lactamases reveals discriminating structural features between B1 types
Authors: Cadag Eithon , Vitalis Elizabeth , Lennox Kristin P , Zhou Carol L Ecale , Zemla Adam T
Published: February 2012

Background

Genes conferring antibiotic resistance to groups of bacterial pathogens are cause for considerable concern, as many once-reliable antibiotics continue to see a reduction in efficacy. The recent discovery of the metallo β-lactamase blaNDM-1 gene, which appears to grant antibiotic resistance to a variety of Enterobacteriaceae via a mobile plasmid, is one example of this distressing trend. The following work describes a computational analysis of pathogen-borne MBLs that focuses on the structural aspects of characterized proteins.

Results

Using both sequence and structural analyses, we examine residues and structural features specific to various pathogen-borne MBL types. This analysis identifies a linker region within MBL-like folds that may act as a discriminating structural feature between these proteins, and specifically resistance-associated acquirable MBLs. Recently released crystal structures of the newly emerged NDM-1 protein were aligned against related MBL structures using a variety of global and local structural alignment methods, and the overall fold conformation is examined for structural conservation. Conservation appears to be present in most areas of the protein, yet is strikingly absent within a linker region, making NDM-1 unique with respect to a linker-based classification scheme. Variability analysis of the NDM-1 crystal structure highlights unique residues in key regions as well as identifying several characteristics shared with other transferable MBLs.

Conclusions

A discriminating linker region identified in MBL proteins is highlighted and examined in the context of NDM-1 and primarily three other MBL types: IMP-1, VIM-2 and ccrA. The presence of an unusual linker region variant and uncommon amino acid composition at specific structurally important sites may help to explain the unusually broad kinetic profile of NDM-1 and may aid in directing research attention to areas of this protein, and possibly other MBLs, that may be targeted for inactivation or attenuation of enzymatic activity.
Incidence and risk factors of Blastocystis infection in an orphanage in Bangkok, Thailand
Authors: Pipatsatitpong Duangnate , Rangsin Ram , Leelayoova Saovanee , Naaglor Tawee , Mungthin Mathirut
Published: February 2012

Background

Blastocystis sp. is one of the most common intestinal protozoa in humans. Unlike other intestinal parasitic infections such as giardiasis and cryptosporidiosis, the epidemiology of blastocystosis in children who live in crowded settings such as day-care centers and orphanages has been rarely explored.

Methods

A retrospective cohort study was conducted to evaluate incidence and risk factors of Blastocystis infection in an orphanage every two consecutive months during April 2003 to April 2004, in Bangkok, Thailand. Blastocystis sp. was identified using direct simple smear, and in vitro cultivation in Jones' medium.

Results

The incidence rate was 1.8/100 person-months and the independent risk factors associated with Blastocystis infection were age, nutritional status and orphans living in the room where their childcare workers were infected.

Conclusions

Person-to-person transmission was most likely to occur either from orphans to childcare workers or from childcare workers to orphans living in the same room. Universal precautions such as regular hand washing and careful handling of fecally contaminated materials are indicated.
Current management and novel agents for malignant melanoma
Authors: Lee Byung , Mukhi Nikhil , Liu Delong
Published: February 2012

Advanced malignant melanoma remains a challenging cancer. Over the past year, there have been 3 agents approved for treatment of melanoma by Food and Drug Administration. These include pegylated interferon alpha-2b for stage III melanoma, vemurafenib for unresectable or metastatic melanoma with BRAF V600E mutation, and ipilimumab for treatment of unresectable or metastatic melanoma. This review will also update on the development of novel agents, including tyrosine kinase inhibitors and adoptive cellular therapy.
Modulation of CXCR3 ligand secretion by prostaglandin E2 and cyclooxygenase inhibitors in human breast cancer
Authors: Bronger Holger , Kraeft Sara , Schwarz-Boeger Ulrike , Cerny Claudia , Stöckel Alexandra , Avril Stefanie , Kiechle Marion , Schmitt Manfred
Published: February 2012

Introduction

In murine breast cancer models, the two interferon-gamma (IFN-γ) inducible chemokines and CXC-chemokine receptor 3 (CXCR3) receptor ligands, monokine induced by γ-interferon (CXCL9) and interferon-γ-inducible protein-10 (CXCL10) impair tumor growth and metastasis formation through recruitment of natural killer (NK) cells and tumor-suppressive T lymphocytes. In human breast cancer, CXCL9 mRNA overexpression correlates with the number of tumor infiltrating lymphocytes and predicts response to different chemotherapeutic regimens. Raising the intratumoral CXCR3 ligand concentration is therefore a possible way to enhance immune intervention in breast cancer. Little is known, however, about expression levels and regulation of these chemokines in human breast cancer. Since the inhibition of cyclooxygenases (COX) has been shown to reduce tumor growth and incidence of metastases in a lymphocytic and IFN-γ dependent manner, we argued that COX isoenzymes are a pharmacologic target to increase intratumoral CXCR3 ligand concentration in human breast cancer.

Methods

CXCL9 was visualized in breast cancer specimens by immunohistochemistry, expression levels of CXCL9 and cyclooxygenases were determined by ELISA and western blotting, respectively. For regulation studies, Michigan Cancer Foundation-7 (MCF-7) and M.D. Anderson - Metastatic Breast 231 (MDA-MB 231) breast cancer cells were stimulated with IFN-γ with or without prostaglandin E2 (PGE2) or COX inhibitors (indomethacin, acetylsalicylic acid (ASA), celecoxib). CXCR3 ligand release from cells was measured by ELISA.

Results

Within the tumor microenvironment, cancer cells are the major source of CXCL9. PGE2 impairs IFN-γ mediated CXCL9 and CXCL10 release from MCF-7 and MDA-MB 231 cells, and inhibition of endogenous cyclooxygenases by indomethacin or ASA correspondingly increases this secretion. Otherwise, high concentrations of the Cyclooxygenase-2 (COX-2) specific antagonist celecoxib have opposite effects and impair CXCL9 and CXCL10 release. In human breast cancer tissue specimens there is an inverse correlation between COX-2 overexpression and CXCL9 concentration, suggesting that the observed in vitro effects are of importance in vivo as well.

Conclusions

Suppressing endogenous PGE2 synthesis by cyclooxygenase inhibition increases CXCL9 and CXCL10 release from breast cancer cells and is therefore a pharmacologic candidate to enhance intratumoral immune infiltration. Yet, to this end the unselective COX inhibitors ASA and indomethacin seem preferable to celecoxib that at higher concentrations reduces CXCR3 ligand release most probably due to COX independent mechanisms.
Gene expression profiling of primary male breast cancers reveals two unique subgroups and identifies N-acetyltransferase-1 (NAT1) as a novel prognostic biomarker
Authors: Johansson Ida , Nilsson Cecilia , Berglund Pontus , Lauss Martin , Ringnér Markus , Olsson Håkan , Luts Lena , Sim Edith , Thorstensson Sten , Fjällskog Marie-Louise , Hedenfalk Ingrid
Published: February 2012

Introduction

Male breast cancer (MBC) is a rare and inadequately characterized disease. The aim of the present study was to characterize MBC tumors transcriptionally, to classify them into comprehensive subgroups, and to compare them with female breast cancer (FBC).

Methods

A total of 66 clinicopathologically well-annotated fresh frozen MBC tumors were analyzed using Illumina Human HT-12 bead arrays, and a tissue microarray with 220 MBC tumors was constructed for validation using immunohistochemistry. Two external gene expression datasets were used for comparison purposes: 37 MBCs and 359 FBCs.

Results

Using an unsupervised approach, we classified the MBC tumors into two subgroups, luminal M1 and luminal M2, respectively, with differences in tumor biological features and outcome, and which differed from the intrinsic subgroups described in FBC. The two subgroups were recapitulated in the external MBC dataset. Luminal M2 tumors were characterized by high expression of immune response genes and genes associated with estrogen receptor (ER) signaling. Luminal M1 tumors, on the other hand, despite being ER positive by immunohistochemistry showed a lower correlation to genes associated with ER signaling and displayed a more aggressive phenotype and worse prognosis. Validation of two of the most differentially expressed genes, class 1 human leukocyte antigen (HLA) and the metabolizing gene N-acetyltransferase-1 (NAT1), respectively, revealed significantly better survival associated with high expression of both markers (HLA, hazard ratio (HR) 3.6, P = 0.002; NAT1, HR 2.5, P = 0.033). Importantly, NAT1 remained significant in a multivariate analysis (HR 2.8, P = 0.040) and may thus be a novel prognostic marker in MBC.

Conclusions

We have detected two unique and stable subgroups of MBC with differences in tumor biological features and outcome. They differ from the widely acknowledged intrinsic subgroups of FBC. As such, they may constitute two novel subgroups of breast cancer, occurring exclusively in men, and which may consequently require novel treatment approaches. Finally, we identified NAT1 as a possible prognostic biomarker for MBC, as suggested by NAT1 positivity corresponding to better outcome.
Prospective Study of Factors Predicting Adherence to Surveillance Mammography in Women Treated for Breast Cancer
Authors: Shelby Rebecca A. , Scipio Cindy D. , Somers Tamara J. , Soo Mary Scott , Weinfurt Kevin P. , Keefe Francis J.
Published: February 2012

Purpose

This prospective study examined the factors that predicted sustained adherence to surveillance mammography in women treated for breast cancer.

Methods

Breast cancer survivors (N = 204) who were undergoing surveillance mammography completed questionnaires assessing mammography-related anticipatory anxiety, persistent breast pain, mammography pain, and catastrophic thoughts about mammography pain. Adherence to mammography in the following year was assessed.

Results

In the year after study entry, 84.8% of women (n = 173) returned for a subsequent mammogram. Unadjusted associations showed that younger age, shorter period of time since surgery, and having upper extremity lymphedema were associated with lower mammography adherence. Forty percent of women reported moderate to high levels of mammography pain (score of ≥ 5 on a 0 to 10 scale). Although mammography pain was not associated with adherence, higher levels of mammography-related anxiety and pain catastrophizing were associated with not returning for a mammogram (P < .05). The impact of anxiety on mammography use was mediated by pain catastrophizing (indirect effect, P < .05).

Conclusion

Findings suggest that women who are younger, closer to the time of surgery, or have upper extremity lymphedema may be less likely to undergo repeated mammograms. It may be important for health professionals to remind selected patients directly that some women avoid repeat mammography and to re-emphasize the value of mammography for women with a history of breast cancer. Teaching women behavioral techniques (eg, redirecting attention) or providing medication for reducing anxiety could be considered for women with high levels of anxiety or catastrophic thoughts related to mammography.
Chronic Lymphocytic Leukemia Is Associated With Decreased Survival of Patients With Malignant Melanoma and Merkel Cell Carcinoma in a SEER Population-Based Study
Authors: Brewer Jerry D. , Shanafelt Tait D. , Otley Clark C. , Roenigk Randall K. , Cerhan James R. , Kay Neil E. , Weaver Amy L. , Call Timothy G.
Published: February 2012

Purpose

To delineate outcomes of malignant melanoma (MM) and Merkel cell carcinoma (MCC) in patients with chronic lymphocytic leukemia (CLL) or non-Hodgkin's lymphoma (NHL).

Patients and Methods

We identified patients with MM or MCC reported to the Surveillance, Epidemiology, and End Results program and analyzed the effects of history of CLL/NHL on overall (OS) and cause-specific survival after MM or MCC. Expected survival was derived from patients with MM or MCC without CLL/NHL.

Results

From 1990 to 2006, 212,245 patients with MM and 3,613 patients with MCC were identified, of whom 1,246 with MM and 90 with MCC had a prior diagnosis of CLL/NHL. Patients with MM and a history of CLL/NHL had worse-than-expected OS as measured by standardized mortality ratio (SMR; SMR for CLL, 2.6; 95% CI, 2.3 to 3.0; SMR for NHL, 2.3; 95% CI, 2.1 to 2.6). MM cause-specific survival was worse than expected for patients with a history of CLL (SMR, 2.8; 95% CI, 2.2 to 3.4) or NHL (SMR, 2.1; 95% CI, 1.7 to 2.6). Among patients with MCC, OS was worse than expected for those with a history of CLL (SMR, 3.1; 95% CI, 2.2 to 4.3) or NHL (SMR, 1.9; 95% CI, 1.3 to 2.8). MCC cause-specific survival was worse than expected for patients with a history of CLL (SMR, 3.8; 95% CI, 2.5 to 5.9), but no difference was observed for NHL (SMR, 0.9; 95% CI, 0.4 to 2.1).

Conclusion

Patients with CLL before diagnosis of MM or MCC have significantly worse OS and MM or MCC cause-specific survival than those without a history of CLL/NHL.
Polyclonal Immunoglobulin Free Light Chain Levels Predict Survival in Myeloid Neoplasms
Authors: Pardanani Animesh , Lasho Terra L. , Finke Christy M. , Rajkumar S. Vincent , Singh Preet Paul , Ketterling Rhett P. , Hanson Curtis A. , Katzmann Jerry A. , Tefferi Ayalew
Published: February 2012

Purpose

We hypothesized that surrogate markers of host immune response may predict survival in myeloid malignancies. Because of immediate practical applicability, we chose plasma immunoglobulin free light chain (FLC) concentration as the biomarker of interest.

Patients and Methods

Two independent cohorts of patients with primary myelofibrosis (PMF) or myelodysplastic syndromes (MDS) were studied. Kappa (κ) and lambda (λ) FLCs were measured by a quantitative nephelometric assay. Patients with monoclonal FLC were excluded.

Results

Values that were above the upper limit of normal for κ or λ FLC were documented in 33% of 240 patients with PMF and 46% of 74 patients with MDS. Increased FLC was significantly associated with increased creatinine, and advanced age in PMF (P < .001) and hemoglobin less than 10 g/dL in MDS (P = .005). In multivariable analysis, increased FLC predicted shortened survival in both PMF and MDS, independent of age, creatinine, and other conventional risk factors. Cutoff levels based on receiver operating characteristic analysis for κ plus λ total FLCs delineated risk groups with highly significant differences in overall survival; International Prognostic Scoring System–adjusted hazard ratio in PMF was 1.9 (95% CI, 1.3 to 2.7), and was 6.3 (95% CI, 2.7 to 16.6) in MDS. No correlations were seen with leukemia-free survival, karyotype, or JAK2, MPL, or IDH mutations. In patients with PMF who were studied by cytokine profiling, the prognostic value of an increased FLC level was independent of that from circulating interleukin-2 receptor (IL-2R) or IL-8 levels.

Conclusion

Increased plasma FLC concentration predicts inferior survival in both PMF and MDS. Its lack of correlation with leukemia-free survival and tumor-specific genetic markers suggests a primarily host-driven biologic phenomenon that might be more broadly applicable.
Querkopf is a key marker of self-renewal and multipotency of adult neural stem cells
Authors: Sheikh Bilal N. , Dixon Mathew P. , Thomas Tim , Voss Anne K.
Published: February 2012

Adult neural stem cells (NSCs) reside in the subventricular zone (SVZ) and produce neurons throughout life. Although their regenerative potential has kindled much interest, few factors regulating NSCs in vivo are known. Among these is the histone acetyltransferase querkopf (QKF, also known as MYST4, MORF, KAT6B), which is strongly expressed in a small subset of cells in the neurogenic subventricular zone. However, the relationship between Qkf gene expression and the hierarchical levels within the neurogenic lineage is currently unknown. We show here that the 10% of SVZ cells with the highest Qkf expression possess the defining NSC characteristics of multipotency and self-renewal and express markers previously shown to enrich for NSCs. A fraction of cells expressing Qkf at medium to high levels is enriched for multipotent progenitor cells with limited self-renewal, followed by a population containing migrating neuroblasts. Cells low in Qkf promoter activity are predominantly ependymal cells. In addition, we show that mice deficient for Bmi1, a central regulator of NSC self-renewal, show an age-dependent decrease in the strongest Qkf-expressing cell population in the SVZ. Our results show a strong relationship between Qkf promoter activity and stem cell characteristics, and a progressive decrease in Qkf gene activity as lineage commitment and differentiation proceed in vivo.
Mammalian erythroblast enucleation requires PI3K-dependent cell polarization
Authors: Wang Junxia , Ramirez Tzutzuy , Ji Peng , Jayapal Senthil Raja , Lodish Harvey F. , Murata-Hori Maki
Published: February 2012

Enucleation, the final step in terminal differentiation of mammalian red blood cells, is an essential process in which the nucleus surrounded by the plasma membrane is budded off from the erythroblast to form a reticulocyte. Most molecular events in enucleation remain unclear. Here we show that enucleation requires establishment of cell polarization that is regulated by the microtubule-dependent local activation of phosphoinositide 3-kinase (PI3K). When the nucleus becomes displaced to one side of the cell, actin becomes restricted to the other side, where dynamic cytoplasmic contractions generate pressure that pushes the viscoelastic nucleus through a narrow constriction in the cell surface, forming a bud. The PI3K products PtdIns(3,4)P2 and PtdIns(3,4,5)P3 are highly localized at the cytoplasmic side of the plasma membrane. PI3K inhibition caused impaired cell polarization, leading to a severe delay in enucleation. Depolymerization of microtubules reduced PI3K activity, resulting in impaired cell polarization and enucleation. We propose that enucleation is regulated by microtubules and PI3K signaling in a manner mechanistically similar to directed cell locomotion.
Interconnected contribution of tissue morphogenesis and the nuclear protein NuMA to the DNA damage response
Authors: Vidi Pierre-Alexandre , Chandramouly Gurushankar , Gray Matthew , Wang Lei , Liu Er , Kim Joseph J. , Roukos Vassilis , Bissell Mina J. , Moghe Prabhas V. , Lelièvre Sophie A.
Published: February 2012

Epithelial tissue morphogenesis is accompanied by the formation of a polarity axis – a feature of tissue architecture that is initiated by the binding of integrins to the basement membrane. Polarity plays a crucial role in tissue homeostasis, preserving differentiation, cell survival and resistance to chemotherapeutic drugs among others. An important aspect in the maintenance of tissue homeostasis is genome integrity. As normal tissues frequently experience DNA double-strand breaks (DSBs), we asked how tissue architecture might participate in the DNA damage response. Using 3D culture models that mimic mammary glandular morphogenesis and tumor formation, we show that DSB repair activity is higher in basally polarized tissues, regardless of the malignant status of cells, and is controlled by hemidesmosomal integrin signaling. In the absence of glandular morphogenesis, in 2D flat monolayer cultures, basal polarity does not affect DNA repair activity but enhances H2AX phosphorylation, an early chromatin response to DNA damage. The nuclear mitotic apparatus protein 1 (NuMA), which controls breast glandular morphogenesis by acting on the organization of chromatin, displays a polarity-dependent pattern and redistributes in the cell nucleus of basally polarized cells upon the induction of DSBs. This is shown using high-content analysis of nuclear morphometric descriptors. Furthermore, silencing NuMA impairs H2AX phosphorylation – thus, tissue polarity and NuMA cooperate to maintain genome integrity.
Endoplasmic reticulum potassium–hydrogen exchanger and small conductance calcium-activated potassium channel activities are essential for ER calcium uptake in neurons and cardiomyocytes
Authors: Kuum Malle , Veksler Vladimir , Liiv Joanna , Ventura-Clapier Renee , Kaasik Allen
Published: February 2012

Calcium pumping into the endoplasmic reticulum (ER) lumen is thought to be coupled to a countertransport of protons through sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) and the members of the ClC family of chloride channels. However, pH in the ER lumen remains neutral, which suggests a mechanism responsible for proton re-entry. We studied whether cation–proton exchangers could act as routes for such a re-entry. ER Ca2+ uptake was measured in permeabilized immortalized hypothalamic neurons, primary rat cortical neurons and mouse cardiac fibers. Replacement of K+ in the uptake solution with Na+ or tetraethylammonium led to a strong inhibition of Ca2+ uptake in neurons and cardiomyocytes. Furthermore, inhibitors of the potassium–proton exchanger (quinine or propranolol) but not of the sodium–proton exchanger reduced ER Ca2+ uptake by 56–82%. Externally added nigericin, a potassium–proton exchanger, attenuated the inhibitory effect of propranolol. Inhibitors of small conductance calcium-sensitive K+ (SKCa) channels (UCL 1684, dequalinium) blocked the uptake of Ca2+ by the ER in all preparations by 48–94%, whereas inhibitors of other K+ channels (IKCa, BKCa and KATP) had no effect. Fluorescence microscopy and western blot analysis revealed the presence of both SKCa channels and the potassium–proton exchanger leucine zipper-EF-hand-containing transmembrane protein 1 (LETM1) in ER in situ and in the purified ER fraction. The data obtained demonstrate that SKCa channels and LETM1 reside in the ER membrane and that their activity is essential for ER Ca2+ uptake.
Efficient synaptic vesicle recycling after intense exocytosis concomitant with the accumulation of non-releasable endosomes at early developmental stages
Authors: Bartolomé-Martín David , Ramírez-Franco Jorge , Castro Enrique , Sánchez-Prieto José , Torres Magdalena
Published: February 2012

Following the exocytosis of neurotransmitter-containing synaptic vesicles, endocytosis is fundamental to re-establishing conditions for synaptic transmission. As there are distinct endocytotic pathways that each differ in their efficiency to generate releasable synaptic vesicles, we used the dye FM1-43 to track vesicle recycling, and to determine whether nerve terminals use multiple pathways of endocytosis. We identified two types of synaptic boutons in cultured cerebellar granule cells that were characterized by weak or strong FM1-43-unloading profiles. Decreasing the extent of exocytosis dramatically increased the proportion of synaptic boutons that exhibited strong FM1-43-unloading and dramatically reduced the number of endosome-like structures. Hence, we concluded that efficient recycling of synaptic vesicles is concomitant with the formation of non-releasable endosomes in both types of synaptic boutons, although to different extents. Furthermore, cell maturation in culture increased the proportion of synaptic boutons that were capable of an intense release response, whereas the chronic blockage of synaptic activity diminished the capacity of boutons to release dye.
Structural organizations of yeast RNase P and RNase MRP holoenzymes as revealed by UV-crosslinking studies of RNA–protein interactions
Authors: Khanova Elena , Esakova Olga , Perederina Anna , Berezin Igor , Krasilnikov Andrey S.
Published: February 2012

Eukaryotic ribonuclease (RNase) P and RNase MRP are closely related ribonucleoprotein complexes involved in the metabolism of various RNA molecules including tRNA, rRNA, and some mRNAs. While evolutionarily related to bacterial RNase P, eukaryotic enzymes of the RNase P/MRP family are much more complex. Saccharomyces cerevisiae RNase P consists of a catalytic RNA component and nine essential proteins; yeast RNase MRP has an RNA component resembling that in RNase P and 10 essential proteins, most of which are shared with RNase P. The structural organizations of eukaryotic RNases P/MRP are not clear. Here we present the results of RNA–protein UV crosslinking studies performed on RNase P and RNase MRP holoenzymes isolated from yeast. The results indicate locations of specific protein-binding sites in the RNA components of RNase P and RNase MRP and shed light on the structural organizations of these large ribonucleoprotein complexes.
Steady-State Simulation with Replication-Dependent Initial Transients: Analysis and Examples
Authors: Argon Nilay Tanık , Andradóttir Sigrún , Alexopoulos Christos , Goldsman David
Published: February 2012

The replicated batch means (RBM) method for steady-state simulation output analysis generalizes both the independent replications (IR) and batch means (BM) methods. We analyze the performance of RBM in situations where the underlying stochastic process possesses an additive initial transient. Our analysis differs from prior work in that the initial transient is stochastic, and hence the sample paths of the transient process may be replication dependent, and possibly also correlated across replications. We provide asymptotic expressions for the mean and variance of the RBM estimators of the steady-state mean and variance parameter of the stochastic process being simulated. We then use our results to study the performance of RBM as a function of the number of replications, initialization method for the replications, and decay rate of the associated initialization bias. Our results provide guidance on when IR, BM, or a combination thereof is the best choice, and also on effective choices of initial states for the replications.
Research Note—The Cost Impact of Spam Filters: Measuring the Effect of Information System Technologies in Organizations
Authors: Caliendo Marco , Clement Michel , Papies Dominik , Scheel-Kopeinig Sabine
Published: February 2012

Dealing with spam is very costly, and many organizations have tried to reduce spam-related costs by installing spam filters. Relying on modern econometric methods to reduce the selection bias of installing a spam filter, we use a unique data setting implemented at a German university to measure the costs associated with spam and the costs savings of spam filters. Our methodological framework accounts for effect heterogeneity and can be easily used to estimate the effect of other IS technologies implemented in organizations.

The majority of costs stem from the time that employees spend identifying and deleting spam, amounting to an average of approximately five minutes per employee per day. Our analysis, which accounts for selection bias, finds that the installation of a spam filter reduces these costs by roughly one third. Failing to account for the selection bias would lead to a result that suggests that installing a spam filter does not reduce working time losses.

However, cost savings only occur when the spam burden is high, indicating that spam filters do not necessarily reduce costs and are therefore no universal remedy. The analysis further shows that spam filters alone are a countermeasure against spam that exhibits only limited effectiveness because they only reduce costs by one third.
Research Note—Using Real Options to Investigate the Market Value of Virtual World Businesses
Authors: Yang Sung-Byung , Lim Jee-Hae , Oh Wonseok , Animesh Animesh , Pinsonneault Alain
Published: February 2012

Virtual worlds are relatively nascent IT platforms with the potential to radically transform business processes and generate significant payoffs. However, in striving to achieve specific outcomes, firms may incur significant risks. Although many companies claim to have attained substantial benefits from their virtual world initiatives, many others have recently scaled down or even abandoned their experimental virtual world projects. This paper assesses the value proposition of virtual world initiatives from the real options perspective. Specifically, we argue that virtual worlds act as a firm's growth option, and we adopt the lens of real options to evaluate the value of this emerging and uncertain technological platform. We employ the event study method to assess the stock market's perception of the future revenue streams of 261 virtual world initiatives announced between 2006 and 2008. Our results indicate that, overall, the market reacts positively to virtual world initiatives. Our findings also show that investors' reactions to virtual world initiatives are contingent on four key characteristics of virtual world initiatives: interpretive flexibility (i.e., technologies that allow managers to experiment), divisibility (i.e., ability to incrementally implement the technology), strategic importance (i.e., an initiative that affects a process of strategic importance to the firm), and exploitable absorptive capacity (i.e., ability to exploit the knowledge acquired through the initiative). We discuss the key implications for real-world practitioners and suggest directions for future research.