New Journal of Science http://www.hindawi.com The latest articles from Hindawi Publishing Corporation © 2014 , Hindawi Publishing Corporation . All rights reserved. Cytolethal Distending Toxin: A Unique Variation on the AB Toxin Paradigm Thu, 25 Sep 2014 12:02:36 +0000 http://www.hindawi.com/journals/njos/2014/249056/ Some of the most potent toxins produced by plants and bacteria are members of a large family known as the AB toxins. AB toxins are generally characterized by a heterogenous complex consisting of two protein chains arranged in various monomeric or polymeric configurations. The newest class within this superfamily is the cytolethal distending toxin (Cdt). The Cdt is represented by a subfamily of toxins produced by a group of taxonomically distinct Gram negative bacteria. Members of this subfamily have a related AB-type chain or subunit configuration and properties distinctive to the AB paradigm. In this review, the unique structural and cytotoxic properties of the Cdt subfamily, target cell specificities, intoxication pathway, modes of action, and relationship to the AB toxin superfamily are compared and contrasted. Joseph M. DiRienzo Copyright © 2014 Joseph M. DiRienzo. All rights reserved. Zingiber officinale (Ginger): A Future Outlook on Its Potential in Prevention and Treatment of Diabetes and Prediabetic States Tue, 23 Sep 2014 12:12:23 +0000 http://www.hindawi.com/journals/njos/2014/674684/ Diabetes is reaching pandemic levels in both developing and developed countries and requires safe, affordable, and effective therapies. This report summarises work in our laboratory on the effects of Zingiber officinale (ginger) and its components in diabetes models and provides a future outlook on the potential for their use in type 2 diabetes. A high fat diet rat model showed modulation of body weight gain and normalisation of glucose and lipid metabolic disturbances, with reduction of insulin resistance in a high fat-high carbohydrate diet model. Ginger extract inhibits enhanced NF-κB in liver of high fat-fed rats through inhibition of the IKK/IκBα/NF-κB classical pathway. The major active component (S)-[6]-gingerol inhibited elevated cytokines in inflamed HuH7 cells through suppression of COX2 expression and protection against the ROS pathway. Ginger extract and gingerols enhanced glucose uptake in L6 myotubes, by enhancing translocation of GLUT4 to the surface membrane and activation of AMPKα1 through a Ca2+/calmodulin-dependent protein kinase kinase pathway. (S)-[6]-Gingerol also enhanced energy metabolism through marked increment of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) gene expression and mitochondrial content in L6 skeletal muscle cells. Future studies will require well designed clinical trials on ginger preparations of defined chemical composition. Basil D. Roufogalis Copyright © 2014 Basil D. Roufogalis. All rights reserved. Regulation of EPCs: The Gateway to Blood Vessel Formation Mon, 22 Sep 2014 08:45:15 +0000 http://www.hindawi.com/journals/njos/2014/972043/ Endothelial progenitor cells (EPCs) are primitive endothelial precursors which are known to functionally contribute to the pathogenesis of disease. To date a number of distinct subtypes of these cells have been described, with differing maturation status, cellular phenotype, and function. Although there is much debate on which subtype constitutes the true EPC population, all subtypes have endothelial characteristics and contribute to neovascularisation. Vasculogenesis, the process by which EPCs contribute to blood vessel formation, can be dysregulated in disease with overabundant vasculogenesis in the context of solid tumours, leading to tumour growth and metastasis, and conversely insufficient vasculogenesis can be present in an ischemic environment. Importantly, it is widely known that transcription factors tightly regulate cellular phenotype and function by controlling the expression of particular target genes and in turn regulating specific signalling pathways. This suggests that transcriptional regulators may be potential therapeutic targets to control EPC function. Herein, we discuss the observed EPC subtypes described in the literature and review recent studies describing the role of a number of transcriptional families in the regulation of EPC phenotype and function in normal and pathological conditions. Kate A. Parham, Stuart M. Pitson, and Claudine S. Bonder Copyright © 2014 Kate A. Parham et al. All rights reserved. Endocrine Resistance in Breast Cancer Wed, 17 Sep 2014 05:07:48 +0000 http://www.hindawi.com/journals/njos/2014/390618/ Around 70% of all breast cancers are estrogen receptor alpha positive and hence their development is highly dependent on estradiol. While the invention of endocrine therapies has revolusioned the treatment of the disease, resistance to therapy eventually occurs in a large number of patients. This paper seeks to illustrate and discuss the complexity and heterogeneity of the mechanisms which underlie resistance and the approaches proposed to combat them. It will also focus on the use and development of methods for predicting which patients are likely to develop resistance. J. M. Dixon Copyright © 2014 J. M. Dixon. All rights reserved. Candida Immunity Mon, 25 Aug 2014 08:33:40 +0000 http://www.hindawi.com/journals/njos/2014/390241/ The human pathogenic fungus Candida albicans is the predominant cause of both superficial and invasive forms of candidiasis. C. albicans primarily infects immunocompromised individuals as a result of either immunodeficiency or intervention therapy, which highlights the importance of host immune defences in preventing fungal infections. The host defence system utilises a vast communication network of cells, proteins, and chemical signals distributed in blood and tissues, which constitute innate and adaptive immunity. Over the last decade the identity of many key molecules mediating host defence against C. albicans has been identified. This review will discuss how the host recognises this fungus, the events induced by fungal cells, and the host innate and adaptive immune defences that ultimately resolve C. albicans infections during health. Julian R. Naglik Copyright © 2014 Julian R. Naglik. All rights reserved. Genetic Dissection of the Physiological Role of Skeletal Muscle in Metabolic Syndrome Tue, 19 Aug 2014 12:08:17 +0000 http://www.hindawi.com/journals/njos/2014/635146/ The primary deficiency underlying metabolic syndrome is insulin resistance, in which insulin-responsive peripheral tissues fail to maintain glucose homeostasis. Because skeletal muscle is the major site for insulin-induced glucose uptake, impairments in skeletal muscle’s insulin responsiveness play a major role in the development of insulin resistance and type 2 diabetes. For example, skeletal muscle of type 2 diabetes patients and their offspring exhibit reduced ratios of slow oxidative muscle. These observations suggest the possibility of applying muscle remodeling to recover insulin sensitivity in metabolic syndrome. Skeletal muscle is highly adaptive to external stimulations such as exercise; however, in practice it is often not practical or possible to enforce the necessary intensity to obtain measurable benefits to the metabolic syndrome patient population. Therefore, identifying molecular targets for inducing muscle remodeling would provide new approaches to treat metabolic syndrome. In this review, the physiological properties of skeletal muscle, genetic analysis of metabolic syndrome in human populations and model organisms, and genetically engineered mouse models will be discussed in regard to the prospect of applying skeletal muscle remodeling as possible therapy for metabolic syndrome. Nobuko Hagiwara Copyright © 2014 Nobuko Hagiwara. All rights reserved. Insights from a Paradigm Shift: How the Poly(A)-Binding Protein Brings Translating mRNAs Full Circle Mon, 18 Aug 2014 07:03:18 +0000 http://www.hindawi.com/journals/njos/2014/873084/ In recent years, our thinking of how the initiation of protein synthesis occurs has changed dramatically. Initiation was thought to involve only events occurring at or near the 5′-cap structure, which serves as the binding site for the cap-binding complex, a group of translation initiation factors (eIFs) that facilitate the binding of the 40 S ribosomal subunit to an mRNA. Because the poly(A)-binding protein (PABP) binds the poly(A) tail present at the 3′-terminus of an mRNA, it was long thought to play no role in translation initiation. In this review, I present evidence from my laboratory that has contributed to the paradigm shift in how we think of mRNAs during translation. The depiction of mRNAs as straight molecules in which the poly(A) tail is far from events occurring at the 5′-end has now been replaced by the concept of a circular mRNA where the interaction between PABP and the cap-binding complex bridges the termini of an mRNA and promotes translation initiation. The research from my laboratory supports the new paradigm that translation of most mRNAs requires a functional and physical interaction between the termini of an mRNA. Daniel R. Gallie Copyright © 2014 Daniel R. Gallie. All rights reserved. Macrophages, Neutrophils, and Cancer: A Double Edged Sword Wed, 13 Aug 2014 09:06:14 +0000 http://www.hindawi.com/journals/njos/2014/271940/ The tumor microenvironment is a well-recognized framework, in which myeloid cells play important roles in cancer development from tumor initiation to metastasis. Immune cells present in the tumor microenvironment can promote or inhibit cancer formation and development. Diversity and plasticity are hallmarks of cells of the monocyte-macrophage lineage. In response to distinct signals the cells of the monocyte-macrophage lineage have the ability to display a wide spectrum of activation states; classical Ml or alternative M2 macrophages represent extremes of a continuum of this activation. Tumor-associated macrophages generally acquire an M2-like phenotype that is relevant for their participation in tumor growth and progression. There is now evidence that also neutrophils can be driven towards distinct phenotypes in response to microenvironmental signals. In fact they can interact with distinct cell populations and produce a wide number of cytokines and effector molecules. Therefore, macrophages and neutrophils are both integrated in the regulation of the innate and adaptive immune responses in various inflammatory situations, including cancer. These findings have triggered efforts to target tumor-associated macrophages and neutrophils. In particular, “reeducation” to activate their antitumor potential or elimination of tumor promoting cells is a new strategy undergoing preclinical and clinical evaluation. Alberto Mantovani Copyright © 2014 Alberto Mantovani. All rights reserved. FLT3 Gene Mutation in Childhood Acute Leukemia: A Preliminary Study Thu, 24 Jul 2014 08:19:02 +0000 http://www.hindawi.com/journals/njos/2014/735453/ Introduction. FLT3 is a tyrosine kinase receptor involved in the proliferation and differentiation of hematopoietic stem cells. There are two types of common FLT3 gene mutation, internal tandem duplication and the D835 mutation, which are known to be associated with a poor clinical outcome in acute leukemia patients. Methods. This study evaluates the incidence of FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) in 38 pediatric patients diagnosed with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) in Hospital Universiti Sains Malaysia. DNA extraction was done from archive bone marrow samples to determine FLT3-ITD mutations using polymerase chain reaction. Results. In this pediatric series, the age ranges were 2–14 years. However, no FLT3-ITD mutations were detected in any of the samples. Conclusion. This preliminary study suggested that the incidence of FLT3 gene mutation most probably was very low in pediatrics patients diagnosed with acute leukemia. A further study with larger number of patient samples is necessary to confirm the findings and to further appreciate the prognostic value of FLT3-ITD mutation among pediatrics patients. Zefarina Zulkafli, Zuraida Zainun, Mohd Nazri Hassan, Wan Suriana Wan Ab Rahman, Nurul Azhan Othman, Selamah Ghazali, and Rosline Hassan Copyright © 2014 Zefarina Zulkafli et al. All rights reserved. Cytochrome c: A Multifunctional Protein Combining Conformational Rigidity with Flexibility Tue, 22 Jul 2014 00:00:00 +0000 http://www.hindawi.com/journals/njos/2014/484538/ Cytochrome has served as a model system for studying redox reactions, protein folding, and more recently peroxidase activity induced by partial unfolding on membranes. This review illuminates some important aspects of the research on this biomolecule. The first part summarizes the results of structural analyses of its active site. Owing to heme-protein interactions the heme group is subject to both in-plane and out-of-plane deformations. The unfolding of the protein as discussed in detail in the second part of this review can be induced by changes of pH and temperature and most prominently by the addition of denaturing agents. Both the kinetic and thermodynamic folding and unfolding involve intermediate states with regard to all unfolding conditions. If allowed to sit at alkaline pH (11.5) for a week, the protein does not return to its folding state when the solvent is switched back to neutral pH. It rather adopts a misfolded state that is prone to aggregation via domain swapping. On the surface of cardiolipin containing liposomes, the protein can adopt a variety of partially unfolded states. Apparently, ferricytochrome c can perform biological functions even if it is only partially folded. Reinhard Schweitzer-Stenner Copyright © 2014 Reinhard Schweitzer-Stenner. All rights reserved. The Unravelled Link between Chronic Kidney Disease and Hepatitis C Infection Thu, 03 Jul 2014 00:00:00 +0000 http://www.hindawi.com/journals/njos/2014/180203/ The 2011 report of the World Health Organization General Assembly on noncommunicable diseases identified chronic kidney disease as a worldwide health issue posing a heavy economic burden. Hepatitis C virus infection, which is responsible for over 1 million deaths resulting from cirrhosis and liver cancer, is linked to chronic kidney disease in several ways; some forms of renal disease are precipitated by hepatitis C and patients with end-stage chronic renal disease are at increased risk for acquiring HCV. The aim of this review is to update the evidence on the relationship between hepatitis C infection and chronic kidney disease. Information has been accumulated in the last decade indicating that HCV plays an adverse effect on the incidence and progression of chronic kidney disease; a novel meta-analysis of observational studies (seven longitudinal studies; 890,560 unique individuals) found a relationship between hepatitis C seropositivity and incidence of reduced estimated glomerular filtration rate (adjusted relative risk, 1.70; 95% CI, 1.20; 2.39; ) in the adult general population. In addition to conventional risk factors, hepatitis C may be an additional factor for the development of chronic kidney disease, and an atheromasic activity of hepatitis C virus has been mentioned. The link between hepatitis C and atherosclerosis could also explain the excess risk of cardiovascular mortality that has been observed among hepatitis C virus seropositive patients undergoing maintenance dialysis. A number of biologically plausible mechanisms related to hepatitis C virus have been hypothesized to contribute to atherosclerosis. Implementation of effective treatment intervention towards hepatitis C is required to decrease the healthcare burden of hepatitis C and to prevent the progression of chronic renal disease. Fabrizio Fabrizi, Piergiorgio Messa, and Paul Martin Copyright © 2014 Fabrizio Fabrizi et al. All rights reserved. Biomimetic-Inspired Infrared Sensors from Microwires: Study of Their Photoconductivity and Infrared Spectrum Properties Thu, 26 Jun 2014 14:02:56 +0000 http://www.hindawi.com/journals/njos/2014/524042/ The fire beetle, Melanophila acuminata (Coleoptera: Buprestidae), senses infrared radiation at wavelengths of 3 and 10–25 microns via specialized protein-containing sensilla. Although the protein denatures outside of a biological system, this detection mechanism has inspired our bottom-up approach to produce single zinc phosphide microwires via vapour transport for IR sensing. The Zn3P2 microwires were immobilized and electrical contact was made by dielectrophoresis. Photoconductivity measurements have been extended to the near IR range, spanning the Zn3P2 band gaps. Purity and integrity of the Zn3P2 microwires including infrared light scattering properties were confirmed by infrared transmission microscopy. This biomimetic microwire shows promise for infrared chip development. M. Israelowitz, B. Weyand, C. Leiterer, V. Munoz, C. Martinez-Tomas, M. Herraiz-Llacer, I. Slowik, C. Beleites, W. Fritzsche, C. Krafft, T. Henkel, M. Reuter, S. W. H. Rizvi, C. Gille, K. Reimers, P. M. Vogt, and H. P. von Schroeder Copyright © 2014 M. Israelowitz et al. All rights reserved. Myocardial Reprogramming Medicine: The Development, Application, and Challenge of Induced Pluripotent Stem Cells Mon, 16 Jun 2014 00:00:00 +0000 http://www.hindawi.com/journals/njos/2014/756240/ Induced pluripotent stem cells (iPSCs) can be generated by reprogramming of adult/somatic cells. The somatic cell reprogramming technology offers a promising strategy for patient-specific cardiac regenerative medicine, disease modeling, and drug discovery. iPSCs are an ideal potential option for an autologous cell source, as compared to other stem/progenitor cells, because they can be propagated indefinitely and are able to generate a large number of functional cardiovascular cells. However, there are concerns about the specificity, efficiency, immunogenicity, and safety of iPSCs which are major challenges in current translational studies. In order to bring iPSC technology closer to clinical use, fundamental changes in this technique are required to ensure that therapeutic progenies are functional and nontumorigenic. It is therefore critical to understand and investigate the biology, genetic, and epigenetic mechanisms of iPSCs generation and differentiation. In this spotlight paper the discovery, history, and relative mechanisms of iPSC generation are summarized. The current technological improvements and potential applications are highlighted along with the important challenges and perspectives. Finally, emerging technologies are presented in which improvements to iPSC generation and differentiation approaches might warrant further investigation, such as integration-free approaches, direct reprogramming, and the development of iPSC banking. Yigang Wang Copyright © 2014 Yigang Wang. All rights reserved. Human Cytomegalovirus Latency: Targeting Differences in the Latently Infected Cell with a View to Clearing Latent Infection Wed, 04 Jun 2014 09:06:15 +0000 http://www.hindawi.com/journals/njos/2014/313761/ Human cytomegalovirus (HCMV) is a human herpesvirus which causes little or no disease in the immunocompetent. However, in immunocompromised individuals, neonates, or patients on immune suppressive therapies, HCMV can cause significant morbidity and mortality in some patient groups. As with all herpesviruses, HCMV has two life cycle phases: a productive phase, where new virions are produced and a latent phase where there is a restricted gene transcription profile and no new virion production. Currently available antivirals target the productive phase of HCMV infection and, although these have greatly decreased the severity of HCMV-induced disease in immunocompromised or immunosuppressed individuals, they often have associated toxicities, routinely result in selection of drug resistant viral mutants, and, importantly, they do not target cells latently infected with virus. Thus, there is a real need to derive novel antiviral therapies which, not least, are also able to target latent infection. In this paper, we describe recent work which has begun to analyse changes in the cell associated with latent infection and the possibility that these latency-associated changes in cell phenotype could be targeted by novel chemo- or immunotherapeutic strategies in order to diminish, or even clear, latent infection at least in some specific clinical settings. Emma Poole, Mark Wills, and John Sinclair Copyright © 2014 Emma Poole et al. All rights reserved. Pax4 and Arx Represent Crucial Regulators of the Development of the Endocrine Pancreas Thu, 29 May 2014 12:10:31 +0000 http://www.hindawi.com/journals/njos/2014/981569/ The development of the endocrine pancreas is under the control of highly orchestrated, cross-interacting transcription factors. Pancreas genesis is initiated by the emergence of a Pdx1/Ptf1a marked territory at the foregut/midgut junction. A small fraction of pancreatic fated cells activates the expression of the bHLH transcription factor Ngn3 triggering the endocrine cell program, thus giving rise to beta-, alpha-, delta-, PP-, and epsilon-cells, producing insulin, glucagon, somatostatin, pancreatic polypeptide, and ghrelin, respectively. Two transcription factors, Pax4 and Arx, play a crucial role in differential endocrine cell subtype specification. They were shown to be necessary and sufficient to endow endocrine progenitors with either a beta- or alpha-cell destiny. Interestingly, whereas the forced expression of Arx in beta-cells converts these into cells exhibiting alpha- and PP-cell characteristics, the sole expression of Pax4 in alpha-cells promotes alpha-cell-neogenesis and the acquisition of beta-cell features, the resulting beta-like cells being capable of counteracting chemically induced diabetes. Gaining new insights into the molecular mechanisms controlling Pax4 and Arx expression in the endocrine pancreas may therefore pave new avenues for the therapy of diabetes. Monica Courtney, Tamara Rabe, Patrick Collombat, and Ahmed Mansouri Copyright © 2014 Monica Courtney et al. All rights reserved. Nucleoporin Gene Fusions and Hematopoietic Malignancies Tue, 27 May 2014 05:36:43 +0000 http://www.hindawi.com/journals/njos/2014/468306/ Nuclear pore complexes (NPCs) are the sole gateways between the nucleus and the cytoplasm of eukaryotic cells and they mediate all macromolecular trafficking between these cellular compartments. Nucleocytoplasmic transport is highly selective and precisely regulated and as such an important aspect of normal cellular function. Defects in this process or in its machinery have been linked to various human diseases, including cancer. Nucleoporins, which are about 30 proteins that built up NPCs, are critical players in nucleocytoplasmic transport and have also been shown to be key players in numerous other cellular processes, such as cell cycle control and gene expression regulation. This review will focus on the three nucleoporins Nup98, Nup214, and Nup358. Common to them is their significance in nucleocytoplasmic transport, their multiple other functions, and being targets for chromosomal translocations that lead to haematopoietic malignancies, in particular acute myeloid leukaemia. The underlying molecular mechanisms of nucleoporin-associated leukaemias are only poorly understood but share some characteristics and are distinguished by their poor prognosis and therapy outcome. Birthe Fahrenkrog Copyright © 2014 Birthe Fahrenkrog. All rights reserved. Regulations of P-Glycoprotein/ABCB1/MDR1 in Human Cancer Cells Tue, 20 May 2014 05:35:49 +0000 http://www.hindawi.com/journals/njos/2014/476974/ Multidrug resistance (MDR) in cancer cells is a phenotype whereby cells display reduced sensitivity to anticancer drugs, based on a variety of mechanisms, including an increase in drug efflux, the reduction of drug uptake, the activation of cell growth and survival signaling, the promotion of DNA repair, and the inhibition of apoptosis signaling. Increased expression of the plasma membrane drug efflux pumps, the ATP-binding cassette (ABC) transporters, is involved in MDR. P-Glycoprotein/ABCB1 is a member of the ABC transporter family, and facilitates the efflux of various anticancer drugs, including anthracyclines, vinca alkaloids, epipodophyllotoxins, taxanes, and kinase inhibitors, from cells. P-Glycoprotein is also expressed in normal tissues and cells, including the kidney, liver, colon, and adrenal gland, to transport and/or secrete substrates and at the blood-brain, blood-placenta, and blood-testis barriers to protect these tissues from toxic substances. To understand the mechanistic functions of P-glycoprotein and to overcome MDR, investigators have identified the substrates and competitive inhibitors of P-glycoprotein. Recently, we and other groups reported associations between cellular signaling pathways and the expression, stability, degradation, localization, and activity of P-glycoprotein. The present review summarizes the currently available information about the transcriptional and posttranslational regulation of P-glycoprotein expression and function. Kazuhiro Katayama, Kohji Noguchi, and Yoshikazu Sugimoto Copyright © 2014 Kazuhiro Katayama et al. All rights reserved. Protein Kinase C (PKC) Isozymes and Cancer Sun, 04 May 2014 06:08:18 +0000 http://www.hindawi.com/journals/njos/2014/231418/ Protein kinase C (PKC) is a family of phospholipid-dependent serine/threonine kinases, which can be further classified into three PKC isozymes subfamilies: conventional or classic, novel or nonclassic, and atypical. PKC isozymes are known to be involved in cell proliferation, survival, invasion, migration, apoptosis, angiogenesis, and drug resistance. Because of their key roles in cell signaling, PKC isozymes also have the potential to be promising therapeutic targets for several diseases, such as cardiovascular diseases, immune and inflammatory diseases, neurological diseases, metabolic disorders, and multiple types of cancer. This review primarily focuses on the activation, mechanism, and function of PKC isozymes during cancer development and progression. Jeong-Hun Kang Copyright © 2014 Jeong-Hun Kang. All rights reserved. Melanins: Skin Pigments and Much More—Types, Structural Models, Biological Functions, and Formation Routes Tue, 18 Mar 2014 07:36:42 +0000 http://www.hindawi.com/journals/njos/2014/498276/ This review presents a general view of all types of melanin in all types of organisms. Melanin is frequently considered just an animal cutaneous pigment and is treated separately from similar fungal or bacterial pigments. Similarities concerning the phenol precursors and common patterns in the formation routes are discussed. All melanins are formed in a first enzymatically-controlled phase, generally a phenolase, and a second phase characterized by an uncontrolled polymerization of the oxidized intermediates. In that second phase, quinones derived from phenol oxidation play a crucial role. Concerning functions, all melanins show a common feature, a protective role, but they are not merely photoprotective pigments against UV sunlight. In pathogenic microorganisms, melanization becomes a virulence factor since melanin protects microbial cells from defense mechanisms in the infected host. In turn, some melanins are formed in tissues where sunlight radiation is not a potential threat. Then, their redox, metal chelating, or free radical scavenging properties are more important than light absorption capacity. These pigments sometimes behave as a double-edged sword, and inhibition of melanogenesis is desirable in different cells. Melanin biochemistry is an active field of research from dermatological, biomedical, cosmetical, and microbiological points of view, as well as fruit technology. F. Solano Copyright © 2014 F. Solano. All rights reserved. Advances and Prospects in Cancer Immunotherapy Thu, 13 Mar 2014 09:59:25 +0000 http://www.hindawi.com/journals/njos/2014/745808/ Cancer immunotherapy is a promising and effective treatment modality for patients with cancers. Cytokine, anticytokine, and antibody therapies appear to be effective in treating various forms of cancer. The human papillomavirus vaccine is protective for cervical cancer, and this discovery has paved the way to the development of cancer vaccines for other forms of virus-associated cancers such as liver cancer and Merkel cell carcinoma. Clinical trials have demonstrated that adoptive cell therapy using tumor-infiltrating lymphocytes can induce tumor regression in approximately 75% of metastatic melanoma patients, suggesting the possibility of using similar technique to effectively treat breast, lung, and renal cancers in the near future. Besides, genetically engineered T cells transduced with genes encoding specific T cell receptors and chimeric antigen receptors have been shown effective in the treatment of cancer patients. These studies suggest that combination therapies are superior choices in cancer immunotherapy for patients. Juhua Zhou Copyright © 2014 Juhua Zhou. All rights reserved. Programmed Cell Death in Neurospora crassa Sun, 02 Mar 2014 13:59:28 +0000 http://www.hindawi.com/journals/njos/2014/479015/ Programmed cell death has been studied for decades in mammalian cells, but simpler organisms, including prokaryotes, plants, and fungi, also undergo regulated forms of cell death. We highlight the usefulness of the filamentous fungus Neurospora crassa as a model organism for the study of programmed cell death. In N. crassa, cell death can be triggered genetically due to hyphal fusion between individuals with different allelic specificities at het loci, in a process called “heterokaryon incompatibility.” Chemical induction of cell death can also be achieved upon exposure to death-inducing agents like staurosporine, phytosphingosine, or hydrogen peroxide. A summary of the recent advances made by our and other groups on the discovery of the mechanisms and mediators underlying the process of cell death in N. crassa is presented. A. Pedro Gonçalves and Arnaldo Videira Copyright © 2014 A. Pedro Gonçalves and Arnaldo Videira. All rights reserved. Mammalian MYC Proteins and Cancer Sun, 02 Feb 2014 13:50:41 +0000 http://www.hindawi.com/journals/njos/2014/757534/ The MYC family of proteins is a group of basic-helix-loop-helix-leucine zipper transcription factors that feature prominently in cancer. Overexpression of MYC is observed in the vast majority of human malignancies and promotes an extraordinary set of changes that impact cell proliferation, growth, metabolism, DNA replication, cell cycle progression, cell adhesion, differentiation, and metastasis. The purpose of this review is to introduce the reader to the mammalian family of MYC proteins, highlight important functional properties that endow them with their potent oncogenic potential, describe their mechanisms of action and of deregulation in cancer cells, and discuss efforts to target the unique properties of MYC, and of MYC-driven tumors, to treat cancer. William P. Tansey Copyright © 2014 William P. Tansey. All rights reserved. Between Amyloids and Aggregation Lies a Connection with Strength and Adhesion Sun, 02 Feb 2014 00:00:00 +0000 http://www.hindawi.com/journals/njos/2014/815102/ We tell of a journey that led to discovery of amyloids formed by yeast cell adhesins and their importance in biofilms and host immunity. We begin with the identification of the adhesin functional amyloid-forming sequences that mediate fiber formation in vitro. Atomic force microscopy and confocal microscopy show 2-dimensional amyloid “nanodomains” on the surface of cells that are activated for adhesion. These nanodomains are arrays of adhesin molecules that bind multivalent ligands with high avidity. Nanodomains form when adhesin molecules are stretched in the AFM or under laminar flow. Treatment with anti-amyloid perturbants or mutation of the amyloid sequence prevents adhesion nanodomain formation and activation. We are now discovering biological consequences. Adhesin nanodomains promote formation and maintenance of biofilms, which are microbial communities. Also, in abscesses within candidiasis patients, we find adhesin amyloids on the surface of the fungi. In both human infection and a Caenorhabditis elegans infection model, the presence of fungal surface amyloids elicits anti-inflammatory responses. Thus, this is a story of how fungal adhesins respond to extension forces through formation of cell surface amyloid nanodomains, with key consequences for biofilm formation and host responses. Peter N. Lipke, Caleen Ramsook, Melissa C. Garcia-Sherman, Desmond N. Jackson, Cho X. J. Chan, Michael Bois, and Stephen A. Klotz Copyright © 2014 Peter N. Lipke et al. All rights reserved. Biology of the KCNQ1 Potassium Channel Wed, 29 Jan 2014 08:34:05 +0000 http://www.hindawi.com/journals/njos/2014/237431/ Ion channels are essential for basic cellular function and for processes including sensory perception and intercellular communication in multicellular organisms. Voltage-gated potassium (Kv) channels facilitate dynamic cellular repolarization during an action potential, opening in response to membrane depolarization to facilitate K+ efflux. In both excitable and nonexcitable cells other, constitutively active, K+ channels provide a relatively constant repolarizing force to control membrane potential, ion homeostasis, and secretory processes. Of the forty known human Kv channel pore-forming α subunits that coassemble in various combinations to form the fundamental tetrameric channel pore and voltage sensor module, KCNQ1 is unique. KCNQ1 stands alone in having the capacity to form either channels that are voltage-dependent and require membrane depolarization for activation, or constitutively active channels. In mammals, KCNQ1 regulates processes including gastric acid secretion, thyroid hormone biosynthesis, salt and glucose homeostasis, and cell volume and in some species is required for rhythmic beating of the heart. In this review, the author discusses the unique functional properties, regulation, cell biology, diverse physiological roles, and involvement in human disease states of this chameleonic K+ channel. Geoffrey W. Abbott Copyright © 2014 Geoffrey W. Abbott. All rights reserved. Vacuolar H+-ATPase: An Essential Multitasking Enzyme in Physiology and Pathophysiology Thu, 23 Jan 2014 14:16:42 +0000 http://www.hindawi.com/journals/njos/2014/675430/ Vacuolar H+-ATPases (V-ATPases) are large multisubunit proton pumps that are required for housekeeping acidification of membrane-bound compartments in eukaryotic cells. Mammalian V-ATPases are composed of 13 different subunits. Their housekeeping functions include acidifying endosomes, lysosomes, phagosomes, compartments for uncoupling receptors and ligands, autophagosomes, and elements of the Golgi apparatus. Specialized cells, including osteoclasts, intercalated cells in the kidney and pancreatic beta cells, contain both the housekeeping V-ATPases and an additional subset of V-ATPases, which plays a cell type specific role. The specialized V-ATPases are typically marked by the inclusion of cell type specific isoforms of one or more of the subunits. Three human diseases caused by mutations of isoforms of subunits have been identified. Cancer cells utilize V-ATPases in unusual ways; characterization of V-ATPases may lead to new therapeutic modalities for the treatment of cancer. Two accessory proteins to the V-ATPase have been identified that regulate the proton pump. One is the (pro)renin receptor and data is emerging that indicates that V-ATPase may be intimately linked to renin/angiotensin signaling both systemically and locally. In summary, V-ATPases play vital housekeeping roles in eukaryotic cells. Specialized versions of the pump are required by specific organ systems and are involved in diseases. L. Shannon Holliday Copyright © 2014 L. Shannon Holliday. All rights reserved. Tumour Immunogenicity, Antigen Presentation, and Immunological Barriers in Cancer Immunotherapy Sun, 05 Jan 2014 09:04:37 +0000 http://www.hindawi.com/journals/njos/2014/734515/ Since the beginning of the 20th century, scientists have tried to stimulate the antitumour activities of the immune system to fight against cancer. However, the scientific effort devoted on the development of cancer immunotherapy has not been translated into the expected clinical success. On the contrary, classical antineoplastic treatments such as surgery, radiotherapy, and chemotherapy are the first line of treatment. Nevertheless, there is compelling evidence on the immunogenicity of cancer cells and the capacity of the immune system to expand cancer-specific effector cytotoxic T cells. However, the effective activation of anticancer T cell responses strongly depends on efficient tumour antigen presentation from professional antigen presenting cells such as dendritic cells (DCs). Several strategies have been used to boost DC antigen presenting functions, but at the end cancer immunotherapy is not as effective as would be expected according to preclinical models. In this review, we comment on these discrepancies, focusing our attention on the contribution of regulatory T cells and myeloid-derived suppressor cells to the lack of therapeutic success of DC-based cancer immunotherapy. David Escors Copyright © 2014 David Escors. All rights reserved.