bluuebunny/crossref_metadata_2025 huggingface dataset:
Examining the Construct Validity of the V-RQOL in Speakers Who Use Alaryngeal Voice
Authors: Bornbaum Catherine C. , Day Adam M. B. , Doyle Philip C.
Published: February 2014

Purpose

The construct validity of the Voice-Related Quality of Life (V-RQOL; Hogikyan & Sethuraman, 1999) measure was evaluated in a sample of 109 individuals who have undergone total laryngectomy.

Method

A principal components factor analysis was performed on participant responses to the 10-question V-RQOL measure.

Results

Factor analysis of the V-RQOL in our alaryngeal sample confirmed the presence of two factors (physical and social–emotional), which is consistent with the identified domains in the current V-RQOL. However, the current data indicate that some of the questions proposed by the original authors of the V-RQOL (Questions 7 and 9) do not align with their proposed domains in this postlaryngectomy sample.

Conclusion

The results indicate that some V-RQOL questions do not align with their proposed domains. Consequently, an alternative scoring algorithm may be warranted for alaryngeal populations, and the authors make suggestions for this change that are simple and efficient. Based on the findings of the present factor analysis, use of this modified scoring procedure may serve to increase the sensitivity of the V-RQOL for those who are laryngectomized and use alaryngeal methods of voice and speech. Consequently, the value and application of the V-RQOL may be expanded in the clinical setting.
Factor XIII Assays and Associated Problems for Laboratory Diagnosis of Factor XIII Deficiency: An Analysis of International Proficiency Testing Results
Authors: Hsu Peihong , Zantek Nicole , Meijer Piet , Hayward Catherine , Brody Judith , Zhang Xinmin , Smock Kristi , Van Cott Elizabeth
Published: February 2014

We analyzed results from the External quality Control of diagnostic Assays and Tests program to assess current clinical laboratory practice and performance of different methods for factor XIII (FXIII) testing internationally. FXIII proficiency testing data from all eight surveys conducted in 2010 and 2011 were analyzed (1,283 results), comparing the three available methods for detecting FXIII deficiency, thus including clot-solubility qualitative activity, quantitative activity, and antigen. Clot-solubility qualitative assays detected a deficiency in only 16% (11/69) of samples with less than 2% FXIII. Assays using added thrombin detected more deficiencies (33%) than did assays without added thrombin (11%). The most commonly used quantitative activity method tended to produce higher results for low FXIII samples than other quantitative activity methods. Antigen results generally showed good accuracy compared with expected levels. The mean interlaboratory coefficients of variation showed wide variability, especially for samples with less than 10% FXIII activity. Laboratory self-classification of results (as normal vs. abnormal) was good, and was slightly better for specimens with ≤ 25% FXIII than for specimens with 26 to 70% or those with >70% FXIII. We conclude that quantitative activity assays perform better for detecting FXIII deficiency than clot solubility assays, although some quantitative activity assays overestimate low FXIII levels.
Coastal flood damage and adaptation costs under 21st century sea-level rise
Authors: Hinkel Jochen , Lincke Daniel , Vafeidis Athanasios T. , Perrette Mahé , Nicholls Robert James , Tol Richard S. J. , Marzeion Ben , Fettweis Xavier , Ionescu Cezar , Levermann Anders
Published: February 2014

Significance

Coastal flood damages are expected to increase significantly during the 21st century as sea levels rise and socioeconomic development increases the number of people and value of assets in the coastal floodplain. Estimates of future damages and adaptation costs are essential for supporting efforts to reduce emissions driving sea-level rise as well as for designing strategies to adapt to increasing coastal flood risk. This paper presents such estimates derived by taking into account a wide range of uncertainties in socioeconomic development, sea-level rise, continental topography data, population data, and adaptation strategies.
XY sex chromosome complement, compared with XX, in the CNS confers greater neurodegeneration during experimental autoimmune encephalomyelitis
Authors: Du Sienmi , Itoh Noriko , Askarinam Sahar , Hill Haley , Arnold Arthur P. , Voskuhl Rhonda R.
Published: February 2014

Significance

Women are more susceptible to multiple sclerosis (MS), but men demonstrate a more progressive disease course. In the MS model, experimental autoimmune encephalomyelitis (EAE), XX as compared with XY, conferred greater encephalitogenic responses. Here, we examined effects of sex chromosomes in the CNS using bone marrow chimeras with XX versus XY CNS and immune systems of the same sex chromosomal type. EAE mice with XY CNS, compared with XX, demonstrated more severe clinical disease with more neurodegeneration in the spinal cord, cerebellum, and cerebral cortex. Expression of the X gene
toll-like receptor 7
, known to induce neuronal damage, was increased in XY mice. These results may bring insight into why men progress faster during a disease characterized by increased susceptibility in women.
Loss of the tumor suppressor LKB1 promotes metabolic reprogramming of cancer cells via HIF-1α
Authors: Faubert Brandon , Vincent Emma E. , Griss Takla , Samborska Bozena , Izreig Said , Svensson Robert U. , Mamer Orval A. , Avizonis Daina , Shackelford David B. , Shaw Reuben J. , Jones Russell G.
Published: February 2014

Significance

Liver kinase B1 (LKB1) is a serine/threonine kinase often inactivated in human cancer. We demonstrate here that loss of LKB1 expression in cancer cells promotes a progrowth metabolic profile that enables increased cell growth and proliferation. Loss of LKB1 promotes increased tumor cell metabolism through mammalian target of rapamycin complex 1- and reactive oxygen species-dependent increases in hypoxia-inducible factor-1α (HIF-1α). LKB1-null cells are dependent on HIF-1α to maintain cellular ATP and viability under poor nutrient conditions, raising the possibility of targeting HIF-1α for synthetic lethality in LKB1-deficient tumors. Together, our data reveal that regulation of cellular metabolism is a key function of LKB1 that may contribute to its tumor-suppressor function in human cancer.
Quasicrystalline tilings with nematic colloidal platelets
Authors: Dontabhaktuni Jayasri , Ravnik Miha , Žumer Slobodan
Published: February 2014

Significance

Complex nematic fluids have the remarkable capability to organize microparticles and nanoparticles into regular structures of various symmetries and dimensionality, according to their micromolecular orientational order. Structures of particles such as chains, clusters, and crystals are found, but no quasicrystals. In this paper, we demonstrate that quasicrystalline structures can be achieved in the form of Penrose tiling by assembling microplatelets in the shape of pentagons within a thin layer of nematic fluid. The tiling is energetically stabilized with binding energies of typically several orders of magnitude higher than thermal energy and further allows for hierarchical substitution of individual pentagonal tiles with smaller tiles, which is interesting for the design of photonics at multiple frequency ranges.
Predicting the spatiotemporal dynamics of hair follicle patterns in the developing mouse
Authors: Cheng Chi Wa , Niu Ben , Warren Mya , Pevny Larysa Halyna , Lovell-Badge Robin , Hwa Terence , Cheah Kathryn S. E.
Published: February 2014

Significance

The establishment of orderly patterns in living systems is fascinating. While the Turing class of reaction–diffusion models defines a paradigm for the emergence of primary patterns, we propose here a much simpler expansion–induction (EI) model for the formation of secondary patterns. The EI model is derived from a simple geometric rule revealed by quantitative analysis of the patterns of secondary hair follicles in the developing mouse. It is driven by the physical growth of the embryo and is able to predict the formation of secondary follicles spatially and temporally, given only the locations of primary follicles. The robustness of the EI model provides an important advance by allowing comparison to real biological patterns beyond the qualitative, visual level.
Ancient west Eurasian ancestry in southern and eastern Africa
Authors: Pickrell Joseph K. , Patterson Nick , Loh Po-Ru , Lipson Mark , Berger Bonnie , Stoneking Mark , Pakendorf Brigitte , Reich David
Published: February 2014

Significance

The hunter–gatherer and pastoralist populations of southern Africa are among the culturally, linguistically, and genetically most diverse human populations. However, little is known about their history. We show that all of these populations have some ancestry most closely related to Europeans and Middle Easterners and use this to reconstruct the history of population movements between Eurasia, eastern Africa, and southern Africa.
ATP turnover by individual myosin molecules hints at two conformers of the myosin active site
Authors: Amrute-Nayak Mamta , Lambeck Katharina-Antonia , Radocaj Ante , Huhnt Helen Elisabeth , Scholz Tim , Hahn Nils , Tsiavaliaris Georgios , Walter Wilhelm J. , Brenner Bernhard
Published: February 2014

Significance

Myosins use adenosine-5′-triphosphate (ATP) hydrolysis to drive motile functions, including muscle contraction. The main steps of ATP hydrolysis were previously identified by solution studies. Observing individual myosin molecules, one by one, interacting with fluorescently-labeled ATP, we found for one and the same myosin molecule two residence times for fluorescent ATP, a long lived, consistent with solution studies, and an unexpected short lived. Kinetic modeling suggests that this results from two active site conformers. In ensemble studies, generation of both dwell times from one myosin molecule had been indistinguishable from generation by a heterogeneous population of myosin molecules, demonstrating the power of molecule-by-molecule analysis to uncover previously undetected kinetic features and to distinguish, for example, different isoforms or mutant from wild-type molecules even in mixed populations.
In vivo imaging of immediate early gene expression reveals layer-specific memory traces in the mammalian brain
Authors: Xie Hong , Liu Yu , Zhu Youzhi , Ding Xinlu , Yang Yuhao , Guan Ji-Song
Published: February 2014

Significance

This study demonstrates how sensory information is represented and stored in cortical circuits during complex behavior in the mammalian brain. Using a newly established automatic algorithm for cell detection, we tracked the expression of immediate early genes from more than 20,000 neurons in each living mouse for 2 mo, revealing quantitative signal changes in each neuron within a local cortical circuit. A natural behavioral task induced sparse and task-specific neuronal activation in cortical layer II. The gradually formed sparse activation of neurons was observed in multiple cortical areas. Our results support the concept of consolidation for long-term memory storage in cortical circuits and demonstrate the representation of natural events as sparse coding in the mammalian brain.
PARP1-dependent recruitment of KDM4D histone demethylase to DNA damage sites promotes double-strand break repair
Authors: Khoury-Haddad Hanan , Guttmann-Raviv Noga , Ipenberg Inbal , Huggins David , Jeyasekharan Anand D. , Ayoub Nabieh
Published: February 2014

Significance

Sophisticated DNA damage repair mechanisms are required to fix DNA lesions and preserve the integrity of the genome. This manuscript provides characterization of KDM4D role in promoting the repair of double-strand breaks (DSBs). Our findings show that KDM4D lysine demethylase is swiftly recruited to DNA breakage sites via its C-terminal region in a PARP1-dependent manner. Further, we have uncovered an exciting function of KDM4D in regulating the association of the DNA damage response master kinase, ATM, with chromatin, thus explaining the defective phosphorylation of ATM substrates found in KDM4D-depleted cells. Altogether, this study advances our understanding of the molecular mechanisms that regulate the repair of DSBs, a critical pathway that is essential for maintaining genome integrity.
Convergent evolution in European and Rroma populations reveals pressure exerted by plague on Toll-like receptors
Authors: Laayouni Hafid , Oosting Marije , Luisi Pierre , Ioana Mihai , Alonso Santos , Ricaño-Ponce Isis , Trynka Gosia , Zhernakova Alexandra , Plantinga Theo S. , Cheng Shih-Chin , van der Meer Jos W. M. , Popp Radu , Sood Ajit , Thelma B. K. , Wijmenga Cisca , Joosten Leo A. B. , Bertranpetit Jaume , Netea Mihai G.
Published: February 2014

Significance

This article gives a unique perspective on the impact of evolution on the immune system under pressure by infections, using the special demographic history of Europe in which two populations with different genetic ancestry, Europeans and Rroma (Gypsies), have lived in the same geographic area and have been exposed to similar environmental hazards, including infections. We identified convergent evolution signals in genes from different human populations. Reconstruction of evolutionary history of European populations has identified Toll-like receptor 1 (TLR1)/TLR6/TLR10 as a pattern recognition pathway shaped by convergent evolution by infections, among which plague is a likely cause, influencing the survival of these populations during the infection.
Mapping the diatom redox-sensitive proteome provides insight into response to nitrogen stress in the marine environment
Authors: Rosenwasser Shilo , Graff van Creveld Shiri , Schatz Daniella , Malitsky Sergey , Tzfadia Oren , Aharoni Asaph , Levin Yishai , Gabashvili Alexandra , Feldmesser Ester , Vardi Assaf
Published: February 2014

Significance

Phytoplankton form massive blooms in the oceans that are controlled by nutrients, light availability, and biotic interactions with grazers and viruses. Although phytoplankton were traditionally considered passive drifters with currents here we demonstrate how diatom cells sense and respond to oxidative stress through a redox-sensitive protein network. We further demonstrate the redox sensitivity of nitrogen assimilation, which is essential for diatom blooms in the ocean, and provide compelling evidence for organelle-specific oxidation patterns under nitrogen stress conditions using a genetically encoded redox sensor. We propose that redox regulation of metabolic rates in the response to stress provides a mechanism of acclimation to rapid fluctuations in the chemophysical gradients in the marine environment.
Monoclonal antibody blocking the recognition of an insulin peptide–MHC complex modulates type 1 diabetes
Authors: Zhang Li , Crawford Frances , Yu Liping , Michels Aaron , Nakayama Maki , Davidson Howard W. , Kappler John W. , Eisenbarth George S.
Published: February 2014

Significance

Antigen-specific therapies are lacking for autoimmunity diseases. The recent discovery of the nature of the IAg7–insulin complex that drives type 1 diabetes in nonobese diabetic (NOD) mice has allowed us to create a monoclonal antibody specific for this complex. This antibody delays diabetes development in NOD mice. Given the similarities between IAg7and the human diabetes risk alleles, HLA-DQ2 and HLA-DQ8, this work encourages the development of similar monoclonal antibodies for the treatment of the human disease.
SAC phosphoinositide phosphatases at the tonoplast mediate vacuolar function in
Arabidopsis
Authors: Nováková Petra , Hirsch Sibylle , Feraru Elena , Tejos Ricardo , van Wijk Ringo , Viaene Tom , Heilmann Mareike , Lerche Jennifer , De Rycke Riet , Feraru Mugurel I. , Grones Peter , Van Montagu Marc , Heilmann Ingo , Munnik Teun , Friml Jiří
Published: February 2014

Significance

Polyphosphoinositides (PPIs) are derivatives of the membrane lipid phosphatidylinositol that occur in minor amounts in eukaryotic membranes. PPIs have regulatory effects on various cellular processes, but their roles in plants are currently not well-understood. Plant growth relies largely on turgor-driven cell expansion, which at the subcellular level is linked to vacuolar dynamics. We identified an unknown subgroup of tonoplast-associated enzymes from
Arabidopsis thaliana
, the suppressor of actin 2 (SAC2) to SAC5, that modify PPI levels in plants and influence vacuolar morphology.
Arabidopsis
lines overexpressing or deficient in SAC isoforms display growth aberrations consistent with defective vacuolar function and turgor control. The data hint at PPI-regulated processes in the plant tonoplast and link PPIs to the control of turgor-driven cell expansion and, possibly, other vacuolar functions.
Preleukemic mutations in human acute myeloid leukemia affect epigenetic regulators and persist in remission
Authors: Corces-Zimmerman M. Ryan , Hong Wan-Jen , Weissman Irving L. , Medeiros Bruno C. , Majeti Ravindra
Published: February 2014

Significance

A growing body of evidence has determined that somatic mutations in acute myeloid leukemia (AML) accumulate in self-renewing hematopoietic stem cells (HSCs). Thus, at the time of diagnosis, AML patients harbor preleukemic HSCs containing some, but not all, of the mutations in the downstream leukemia. Despite these findings, common patterns of preleukemic clonal evolution have not been determined, nor has the response of preleukemic HSCs to standard therapy been identified. This report addresses both of these questions determining that there are common patterns of preleukemic clonal evolution in AML, and that these preleukemic HSCs often survive standard induction chemotherapy. This study is of interest to the AML field, and broadly in cancer genomics as the principle that stem cells acquire initial cancer-initiating mutations is likely to extend beyond AML.
Functional architecture of MFSd-glucose transporters
Authors: Madej M. Gregor , Sun Linfeng , Yan Nieng , Kaback H. Ronald
Published: February 2014

Significance

The crystallographic model of the Major Facilitator Superfamily (MFS) member,d-xylose permease XylE fromEscherichia coli, a homologue of humand-glucose transporters, the GLUTs (SLC2), provides a structural framework for the identification and physical localization of crucial residues in transporters with medical relevance (i.e. the GLUTs). The mechanism and substrate specificity of human and prokaryotic sugar transporters are discussed by using homology modeling, molecular docking, and experimentation. Substrate-specificity determinants for XylE, GLUT1, and GLUT5 are proposed. Furthermore, concepts derived from other bacterial MFS transporters are examined for their relevance to the GLUTs by comparing conservation of critical residues. XylE mutants that mimic the characteristics of GLUT1 are tested, revealing that uniport and symport are mechanistically related.
Cartilage-specific deletion of Mig-6 results in osteoarthritis-like disorder with excessive articular chondrocyte proliferation
Authors: Staal Ben , Williams Bart O. , Beier Frank , Vande Woude George F. , Zhang Yu-Wen
Published: February 2014

Significance

Mitogen-inducible gene 6 (Mig-6) was found to be an important factor in maintaining joint homeostasis, and its loss in mice results in the development of an osteoarthritis (OA)-like disorder in multiple synovial joints. However, it was unclear in what cells Mig-6 was expressed and what cells were causal for developing the OA-like phenotype. Here we report that Mig-6 is uniquely expressed in the cells surrounding entire surface of the synovial joint, including chondrocytes in the superficial zone of the articular cartilage and in the meniscus, and synovial lining cells. We found that although chondrocytes play a critical role in developing the OA-like disorder in the knees, other cell types are likely required for full development of the Mig-6–deficient joint phenotype.
Antiviral drug ganciclovir is a potent inhibitor of microglial proliferation and neuroinflammation
Authors: Ding Zhaoqing , Mathur Vidhu , Ho Peggy P. , James Michelle L. , Lucin Kurt M. , Hoehne Aileen , Alabsi Haitham , Gambhir Sanjiv S. , Steinman Lawrence , Luo Jian , Wyss-Coray Tony
Published: February 2014

Aberrant microglial responses contribute to neuroinflammation in many neurodegenerative diseases, but no current therapies target pathogenic microglia. We discovered unexpectedly that the antiviral drug ganciclovir (GCV) inhibits the proliferation of microglia in experimental autoimmune encephalomyelitis (EAE), a mouse model for multiple sclerosis (MS), as well as in kainic acid–induced excitotoxicity. In EAE, GCV largely prevented infiltration of T lymphocytes into the central nervous system (CNS) and drastically reduced disease incidence and severity when delivered before the onset of disease. In contrast, GCV treatment had minimal effects on peripheral leukocyte distribution in EAE and did not inhibit generation of antibodies after immunization with ovalbumin. Additionally, a radiolabeled analogue of penciclovir, [18F]FHBG, which is similar in structure to GCV, was retained in areas of CNS inflammation in EAE, but not in naive control mice, consistent with the observed therapeutic effects. Our experiments suggest GCV may have beneficial effects in the CNS beyond its antiviral properties.
USP21 negatively regulates antiviral response by acting as a RIG-I deubiquitinase
Authors: Fan Yihui , Mao Renfang , Yu Yang , Liu Shangfeng , Shi Zhongcheng , Cheng Jin , Zhang Huiyuan , An Lei , Zhao Yanling , Xu Xin , Chen Zhenghu , Kogiso Mari , Zhang Dekai , Zhang Hong , Zhang Pumin , Jung Jae U. , Li Xiaonan , Xu Guotong , Yang Jianhua
Published: February 2014

Lys63-linked polyubiquitination of RIG-I is essential in antiviral immune defense, yet the molecular mechanism that negatively regulates this critical step is poorly understood. Here, we report that USP21 acts as a novel negative regulator in antiviral responses through its ability to bind to and deubiquitinate RIG-I. Overexpression of USP21 inhibited RNA virus–induced RIG-I polyubiquitination and RIG-I–mediated interferon (IFN) signaling, whereas deletion of USP21 resulted in elevated RIG-I polyubiquitination, IRF3 phosphorylation, IFN-α/β production, and antiviral responses in MEFs in response to RNA virus infection. USP21 also restricted antiviral responses in peritoneal macrophages (PMs) and bone marrow–derived dendritic cells (BMDCs). USP21-deficient mice spontaneously developed splenomegaly and were more resistant to VSV infection with elevated production of IFNs. Chimeric mice with USP21-deficient hematopoietic cells developed virus-induced splenomegaly and were more resistant to VSV infection. Functional comparison of three deubiquitinases (USP21, A20, and CYLD) demonstrated that USP21 acts as a bona fide RIG-I deubiquitinase to down-regulate antiviral response independent of the A20 ubiquitin-editing complex. Our studies identify a previously unrecognized role for USP21 in the negative regulation of antiviral response through deubiquitinating RIG-I.
A New Bayesian Solution to the Paradox of the Ravens
Authors: Rinard Susanna
Published: February 2014

The canonical Bayesian solution to the ravens paradox faces a problem: it entails that black nonravens disconfirm the hypothesis that all ravens are black. I provide a new solution that avoids this problem. On my solution, black ravens confirm that all ravens are black, while nonblack nonravens and black nonravens are neutral. My approach is grounded in certain relations of epistemic dependence, which, in turn, are grounded in the fact that the kind raven is more natural than the kind black. The solution applies to any generalization “All F’s are G” in which F is more natural than G.
What (If Anything) Is Shared in Pain Empathy? A Critical Discussion of De Vignemont and Jacob’s Theory of the Neural Substrate of Pain Empathy
Authors: Michael John , Fardo Francesca
Published: February 2014

In a recent article in Philosophy of Science, De Vignemont and Jacob defend the view that empathy involves interpersonal similarity between an empathizer and a target person with respect to internal affective states. Focusing on empathy for pain, they propose a theory of the neural substrate of pain empathy. We point out several flaws in their interpretation of the data and argue that currently available data do not differentiate between De Vignemont and Jacob’s model and alternative models. Finally, we offer some suggestions about how this might be achieved in future research.
Does “Information” Provide a Compelling Framework for a Theory of Natural Selection? Grounds for Caution
Authors: Sarkar Sahotra
Published: February 2014

Frank has recently argued for an information-theoretic interpretation of natural selection. This interpretation is based on the identification of a measure related to the Malthusian parameter (for population change) with the Jeffreys divergence between the present allelic distribution of the population and that distribution in the next generation. It is pointed out in this analysis that this identification only holds if the mean fitness of the population is a constant, that is, there is no selection. This problem is used to argue for the superiority of the standard dynamical interpretation of natural selection over its information-theoretic counterpart.
Bayesian Measures of Confirmation from Scoring Rules
Authors: van Enk Steven J.
Published: February 2014

I show how scoring rules, interpreted as measuring the inaccuracy of a set of degrees of belief, may be exploited to construct confirmation measures as used in Bayesian confirmation theory. I construct two confirmation measures from two particular standard scoring rules. One of these measures is genuinely new, the second is trivially ordinally equivalent to the difference measure. These two measures are tested against three well-known measures of confirmation in a simple but illuminating case that contains in a natural way the problem of irrelevant conjunction. The genuinely new measure emerges, arguably, as the best.
SegAnnDB: interactive Web-based genomic segmentation
Authors: Hocking Toby D. , Boeva Valentina , Rigaill Guillem , Schleiermacher Gudrun , Janoueix-Lerosey Isabelle , Delattre Olivier , Richer Wilfrid , Bourdeaut Franck , Suguro Miyuki , Seto Masao , Bach Francis , Vert Jean-Philippe
Published: February 2014

Motivation: DNA copy number profiles characterize regions of chromosome gains, losses and breakpoints in tumor genomes. Although many models have been proposed to detect these alterations, it is not clear which model is appropriate before visual inspection the signal, noise and models for a particular profile.

Results: We propose SegAnnDB, a Web-based computer vision system for genomic segmentation: first, visually inspect the profiles and manually annotate altered regions, then SegAnnDB determines the precise alteration locations using a mathematical model of the data and annotations. SegAnnDB facilitates collaboration between biologists and bioinformaticians, and uses the University of California, Santa Cruz genome browser to visualize copy number alterations alongside known genes.

Availability and implementation: The breakpoints project on INRIA GForge hosts the source code, an Amazon Machine Image can be launched and a demonstration Web site is http://bioviz.rocq.inria.fr.

Contact:  toby@sg.cs.titech.ac.jp

Supplementary information:  Supplementary data are available at Bioinformatics online.
An antisense promoter in mouse L1 retrotransposon open reading frame-1 initiates expression of diverse fusion transcripts and limits retrotransposition
Authors: Li Jingfeng , Kannan Manoj , Trivett Anna L. , Liao Hongling , Wu Xiaolin , Akagi Keiko , Symer David E.
Published: February 2014

Between 6 and 30% of human and mouse transcripts are initiated from transposable elements. However, the promoters driving such transcriptional activity are mostly unknown. We experimentally characterized an antisense (AS) promoter in mouse L1 retrotransposons for the first time, oriented antiparallel to the coding strand of L1 open reading frame-1. We found that AS transcription is mediated by RNA polymerase II. Rapid amplification of cDNA ends cloning mapped transcription start sites adjacent to the AS promoter. We identified >100 novel fusion transcripts, of which many were conserved across divergent mouse lineages, suggesting conservation of potential functions. To evaluate whether AS L1 transcription could regulate L1 retrotransposition, we replaced portions of native open reading frame-1 in donor elements by synonymously recoded sequences. The resulting L1 elements lacked AS promoter activity and retrotransposed more frequently than endogenous L1s. Overexpression of AS L1 transcripts also reduced L1 retrotransposition. This suppression of retrotransposition was largely independent of Dicer. Our experiments shed new light on how AS fusion transcripts are initiated from endogenous L1 elements across the mouse genome. Such AS transcription can contribute substantially both to natural transcriptional variation and to endogenous regulation of L1 retrotransposition.
Anesthesia-related Cardiac Arrest
Authors: Ellis Sheila J. , Newland Myrna C. , Simonson Jean A. , Peters K. Reed , Romberger Debra J. , Mercer David W. , Tinker John H. , Harter Ronald L. , Kindscher James D. , Qiu Fang , Lisco Steven J.
Published: February 2014

Background:

Much is still unknown about the actual incidence of anesthesia-related cardiac arrest in the United States.

Methods:

The authors identified all of the cases of cardiac arrest from their quality improvement database from 1999 to 2009 and submitted them for review by an independent study commission to give them the best estimate of anesthesia-related cardiac arrest at their institution. One hundred sixty perioperative cardiac arrests within 24 h of surgery were identified from an anesthesia database of 217,365 anesthetics. An independent study commission reviewed all case abstracts to determine which cardiac arrests were anesthesia-attributable or anesthesia-contributory. Anesthesia-attributable cardiac arrests were those cases in which anesthesia was determined to be the primary cause of cardiac arrest. Anesthesia-contributory cardiac arrests were those cases where anesthesia was determined to have contributed to the cardiac arrest.

Results:

Fourteen cardiac arrests were anesthesia-attributable, resulting in an incidence of 0.6 per 10,000 anesthetics (95% CI, 0.4 to 1.1). Twenty-three cardiac arrests were found to be anesthesia-contributory resulting in an incidence of 1.1 per 10,000 anesthetics (95% CI, 0.7 to 1.6). Sixty-four percent of anesthesia-attributable cardiac arrests were caused by airway complications that occurred primarily with induction, emergence, or in the postanesthesia care unit, and mortality was 29%. Anesthesia-contributory cardiac arrest occurred during all phases of the anesthesia, and mortality was 70%.

Conclusion:

As judged by an independent study commission, anesthesia-related cardiac arrest occurred in 37 of 160 cardiac arrests within the 24-h perioperative period.
Role of pHi, and proton transporters in oncogene-driven neoplastic transformation
Authors: Reshkin Stephan Joel , Greco Maria Raffaella , Cardone Rosa Angela
Published: February 2014

The change of a normal, healthy cell to a transformed cell is the first step in the evolutionary arc of a cancer. While the role of oncogenes in this ‘passage’ is well known, the role of ion transporters in this critical step is less known and is fundamental to our understanding the early physiological processes of carcinogenesis. Cancer cells and tissues have an aberrant regulation of hydrogen ion dynamics leading to a reversal of the normal tissue intracellular to extracellular pH gradient (ΔpHito ΔpHe). When this perturbation in pH dynamics occurs during carcinogenesis is less clear. Very early studies using the introduction of different oncogene proteins into cells observed a concordance between neoplastic transformation and a cytoplasmic alkalinization occurring concomitantly with a shift towards glycolysis in the presence of oxygen, i.e. ‘Warburg metabolism’. These processes may instigate a vicious cycle that drives later progression towards fully developed cancer where the reversed pH gradient becomes ever more pronounced. This review presents our understanding of the role of pH and the NHE1 in driving transformation, in determining the first appearance of the cancer ‘hallmark’ characteristics and how the use of pharmacological approaches targeting pH/NHE1 may open up new avenues for efficient treatments even during the first steps of cancer development.
Interaction of tumour cells with their microenvironment: ion channels and cell adhesion molecules. A focus on pancreatic cancer
Authors: Arcangeli Annarosa , Crociani Olivia , Bencini Lapo
Published: February 2014

Cancer must be viewed as a ‘tissue’, constituted of both transformed cells and a heterogeneous microenvironment, the ‘tumour microenvironment’ (TME). The TME undergoes a complex remodelling during the course of multistep tumourigenesis, hence strongly contributing to tumour progression. Ion channels and transporters (ICTs), being expressed on both tumour cells and in the different cellular components of the TME, are in a strategic position to sense and mediate signals arising from the TME. Often, this transmission is mediated by integrin adhesion receptors, which are the main cellular receptors capable of mediating cell-to-cell and cell-to-matrix bidirectional signalling. Integrins can often operate in conjunction with ICT because they can behave as functional partners of ICT proteins. The role of integrin receptors in the crosstalk between tumour cells and the TME is particularly relevant in the context of pancreatic cancer (PC), characterized by an overwhelming TME which actively contributes to therapy resistance. We discuss the possibility that this occurs through integrins and ICTs, which could be exploited as targets to overcome chemoresistance in PC.
Ion channels and transporters in tumour cell migration and invasion
Authors: Schwab Albrecht , Stock Christian
Published: February 2014

Cell migration is a central component of the metastatic cascade requiring a concerted action of ion channels and transporters (migration-associated transportome), cytoskeletal elements and signalling cascades. Ion transport proteins and aquaporins contribute to tumour cell migration and invasion among other things by inducing local volume changes and/or by modulating Ca2+and H+signalling. Targeting cell migration therapeutically bears great clinical potential, because it is a prerequisite for metastasis. Ion transport proteins appear to be attractive candidate target proteins for this purpose because they are easily accessible as membrane proteins and often overexpressed or activated in cancer. Importantly, a number of clinically widely used drugs are available whose anticipated efficacy as anti-tumour drugs, however, has now only begun to be evaluated.
Functional properties of ion channels and transporters in tumour vascularization
Authors: Fiorio Pla Alessandra , Munaron Luca
Published: February 2014

Vascularization is crucial for solid tumour growth and invasion, providing metabolic support and sustaining metastatic dissemination. It is now accepted that ion channels and transporters play a significant role in driving the cancer growth at all stages. They may represent novel therapeutic, diagnostic and prognostic targets for anti-cancer therapies. On the other hand, although the expression and role of ion channels and transporters in the vascular endothelium is well recognized and subject of recent reviews, only recently has their involvement in tumour vascularization been recognized. Here, we review the current literature on ion channels and transporters directly involved in the angiogenic process. Particular interest will be focused on tumour angiogenesis
in vivo
as well as in the different steps that drive this process
in vitro
, such as endothelial cell proliferation, migration, adhesion and tubulogenesis. Moreover, we compare the ‘transportome’ system of tumour vascular network with the physiological one.
Ion channels and apoptosis in cancer
Authors: Bortner Carl D. , Cidlowski John A.
Published: February 2014

Humans maintain a constant cell number throughout their lifespan. This equilibrium of cell number is accomplished when cell proliferation and cell death are kept balanced, achieving a steady-state cell number. Abnormalities in cell growth or cell death can lead to an overabundance of cells known as neoplasm or tumours. While the perception of cancer is often that of an uncontrollable rate of cell growth or increased proliferation, a decrease in cell death can also lead to tumour formation. Most cells when detached from their normal tissue die. However, cancer cells evade cell death, tipping the balance to an overabundance of cell number. Therefore, overcoming this resistance to cell death is a decisive factor in the treatment of cancer. Ion channels play a critical role in cancer in regards to cell proliferation, malignant angiogenesis, migration and metastasis. Additionally, ion channels are also known to be critical components of apoptosis. In this review, we discuss the modes of cell death focusing on the ability of cancer cells to evade apoptosis. Specifically, we focus on the role ion channels play in controlling and regulating life/death decisions and how they can be used to overcome resistance to apoptosis in the treatment of cancer.
Ion channels in cancer: future perspectives and clinical potential
Authors: Lang Florian , Stournaras Christos
Published: February 2014

Ion transport across the cell membrane mediated by channels and carriers participate in the regulation of tumour cell survival, death and motility. Moreover, the altered regulation of channels and carriers is part of neoplastic transformation. Experimental modification of channel and transporter activity impacts tumour cell survival, proliferation, malignant progression, invasive behaviour or therapy resistance of tumour cells. A wide variety of distinct Ca2+permeable channels, K+channels, Na+channels and anion channels have been implicated in tumour growth and metastasis. Further experimental information is, however, needed to define the specific role of individual channel isoforms critically important for malignancy. Compelling experimental evidence supports the assumption that the pharmacological inhibition of ion channels or their regulators may be attractive targets to counteract tumour growth, prevent metastasis and overcome therapy resistance of tumour cells. This short review discusses the role of Ca2+permeable channels, K+channels, Na+channels and anion channels in tumour growth and metastasis and the therapeutic potential of respective inhibitors.
Nosocomial spread of meticillin-resistant Staphylococcus aureus with β-lactam-inducible arbekacin resistance
Authors: Harada Yukiko , Chong Yong , Shimono Nobuyuki , Miyake Noriko , Uchida Yujiro , Kadowaki Masako , Akashi Koichi , Shimoda Shinji
Published: February 2014

A meticillin-resistant Staphylococcus aureus (MRSA) strain with additional β-lactam-inducible aminoglycoside resistance was previously reported by a group at the Kitasato University in Japan. In addition to gentamicin, the ‘Kitasato strain’ was resistant to arbekacin (ABK), which is primarily used as an anti-MRSA aminoglycoside. No further studies regarding the spread of MRSA strains with the newly identified resistance mechanism have been reported to date. To obtain epidemiological data on MRSA strains with the antagonistic resistance and to analyse their genetic features, we examined the emergence of β-lactam-inducible ABK-resistant MRSA strains at our university hospital using longitudinal analysis. Among the 396 isolates, 35 (8.8 %) were found to be ABK-resistant MRSA strains (the resistance being induced by β-lactams). Moreover, based on the pulsed-field gel electrophoresis profiles, the clonality of those MRSA strains changed at different time periods. In the Kitasato strain, the antagonistic mechanism was clearly demonstrated by the integration of transposable elements; a Tn4001-IS257 hybrid structure that contained an aminoglycoside resistance gene cointegrated into a region downstream of the β-lactamase gene. In most of the MRSA strains detected in our study, the antagonistic interaction was explained by the same mechanism as that found in the Kitasato strain. Interestingly, sequence analysis showed that all of our strains carried IS257 insertion sites which were different from those of the Kitasato strain. This study shows that MRSA strains with the additional antagonistic resistance are not uncommon and have been increasingly disseminating in clinical settings.
Cyanobacterial heat-shock response: role and regulation of molecular chaperones
Authors: Rajaram Hema , Chaurasia Akhilesh Kumar , Apte Shree Kumar
Published: February 2014

Cyanobacteria constitute a morphologically diverse group of oxygenic photoautotrophic microbes which range from unicellular to multicellular, and non-nitrogen-fixing to nitrogen-fixing types. Sustained long-term exposure to changing environmental conditions, during their three billion years of evolution, has presumably led to their adaptation to diverse ecological niches. The ability to maintain protein conformational homeostasis (folding–misfolding–refolding or aggregation–degradation) by molecular chaperones holds the key to the stress adaptability of cyanobacteria. Although cyanobacteria possess several genes encoding DnaK and DnaJ family proteins, these are not the most abundant heat-shock proteins (Hsps), as is the case in other bacteria. Instead, the Hsp60 family of proteins, comprising two phylogenetically conserved proteins, and small Hsps are more abundant during heat stress. The contribution of the Hsp100 (ClpB) family of proteins and of small Hsps in the unicellular cyanobacteria (SynechocystisandSynechococcus) as well as that of Hsp60 proteins in the filamentous cyanobacteria (Anabaena) to thermotolerance has been elucidated. The regulation of chaperone genes by severalcis-elements andtrans-acting factors has also been well documented. Recent studies have demonstrated novel transcriptional and translational (mRNA secondary structure) regulatory mechanisms in unicellular cyanobacteria. This article provides an insight into the heat-shock response: its organization, and ecophysiological regulation and role of molecular chaperones, in unicellular and filamentous nitrogen-fixing cyanobacterial strains.
The protein tyrosine kinases EpsB and PtkA differentially affect biofilm formation in Bacillus subtilis
Authors: Gerwig Jan , Kiley Taryn B. , Gunka Katrin , Stanley-Wall Nicola , Stülke Jörg
Published: February 2014

The Gram-positive soil bacteriumBacillus subtilisis able to choose between motile and sessile lifestyles. The sessile way of life, also referred to as biofilm, depends on the formation of an extracellular polysaccharide matrix and some extracellular proteins. Moreover, a significant proportion of cells in a biofilm form spores. The first two genes of the 15-gene operon for extracellular polysaccharide synthesis,epsAandepsB, encode a putative transmembrane modulator protein and a putative protein tyrosine kinase, respectively, with similarity to the TkmA/PtkA modulator/kinase couple. Here we show that the putative kinase EpsB is required for the formation of structured biofilms. However, anepsBmutant is still able to form biofilms. As shown previously, aptkAmutant is also partially defective in biofilm formation, but this defect is related to spore formation in the biofilm. The absence of both kinases resulted in a complete loss of biofilm formation. Thus, EpsB and PtkA fulfil complementary functions in biofilm formation. The activity of bacterial protein tyrosine kinases depends on their interaction with modulator proteins. Our results demonstrate the specific interaction between the putative kinase EpsB and its modulator protein EpsA and suggest that EpsB activity is stimulated by its modulator EpsA.
Modeling bi-modality improves characterization of cell cycle on gene expression in single cells
Authors: McDavid Andrew , Dennis Lucas , Danaher Patrick , Finak Greg , Krouse Michael , Wang Alice , Webster Philippa , Beechem Joseph , Gottardo Raphael
Published: February 2014

Advances in high-throughput, single cell gene expression are allowing interrogation of cell heterogeneity. However, there is concern that the cell cycle phase of a cell might bias characterizations of gene expression at the single-cell level. We assess the effect of cell cycle phase on gene expression in single cells by measuring 333 genes in 930 cells across three phases and three cell lines. We determine each cell’s phase non-invasively without chemical arrest and use it as a covariate in tests of differential expression. We observe bi-modal gene expression, a previously-described phenomenon, wherein the expression of otherwise abundant genes is either strongly positive, or undetectable within individual cells. This bi-modality is likely both biologically and technically driven. Irrespective of its source, we show that it should be modeled to draw accurate inferences from single cell expression experiments. To this end, we propose a semi-continuous modeling framework based on the generalized linear model, and use it to characterize genes with consistent cell cycle effects across three cell lines. Our new computational framework improves the detection of previously characterized cell-cycle genes compared to approaches that do not account for the bi-modality of single-cell data. We use our semi-continuous modelling framework to estimate single cell gene co-expression networks. These networks suggest that in addition to having phase-dependent shifts in expression (when averaged over many cells), some, but not all, canonical cell cycle genes tend to be co-expressed in groups in single cells. We estimate the amount of single cell expression variability attributable to the cell cycle. We find that the cell cycle explains only 5%-17% of expression variability, suggesting that the cell cycle will not tend to be a large nuisance factor in analysis of the single cell transcriptome.