bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intraarticular and Systemic Inflammatory Profiles May Identify Patients with Osteoarthritis
Authors: Heard Bryan J. , Fritzler Marvin J. , Wiley J. Preston , McAllister Jenelle , Martin Liam , El-Gabalawy Hani , Hart David A. , Frank Cyril B. , Krawetz Roman 
Published: May 2013

Objective.To determine whether cytokine/chemokine profiles from synovial fluid and sera discriminate mild/moderate osteoarthritis (OA) from normal and severe OA cohorts.Methods.Multiplex technology was used to quantify expression levels for 42 cytokines in the synovial fluid of patients diagnosed with severe OA (n = 20) and mild/moderate OA (n = 12), as well as normal controls (n = 34). The same 42 cytokines were examined in serum samples of patients with severe OA (n = 26) and mild/moderate OA (n = 74) and normal individuals (n = 100). Treatment group comparisons followed by principal component analysis (PCA) and K-means clustering of the significantly different cytokines/chemokines revealed groupings of patients by physician diagnosis.Results.Differences in cytokine/chemokine levels were found between control, mild/moderate OA, and severe OA synovial fluid samples, as well as between normal and mild/moderate OA serum samples, and between control and severe OA serum samples. No differences were observed between mild/moderate and severe OA serum samples. Visual groupings based on PCA were validated by K-means analysis, with the best results obtained from the comparison of normal and mild/moderate OA serum samples with 96% of normal and 93% of mild/moderate OA samples accurately identified.Conclusion.Our study suggests that comparing the expression levels of cytokines/chemokines in synovial fluid and/or serum of patients with OA may have promise as a diagnostic platform to identify patients early in their disease course. This high-throughput low-cost assay may be able to provide clinicians with a diagnostic test to complement existing clinical and imaging modalities currently used to diagnose OA.
A Potential Suppressive Effect of Natural Antisense IL-1β RNA on Lipopolysaccharide-Induced IL-1β Expression
Authors: Lu Jiawei , Wu Xiurong , Hong Mao , Tobias Peter , Han Jiahuai 
Published: May 2013

Abstract
Although more than half of genomic loci are believed to have antisense transcription, whether antisense transcription is involved in cytokine expression has not been studied. In this study, we show that some loci of innate immunity related genes do have antisense transcripts. We investigated the effect of several antisense RNAs, including anti–4-1BBL, anti-p100, and anti–IL-1β, on their cognate sense gene’s expression in macrophages. We found that overexpression of antisense IL-1β transcript suppressed IL-1β expression. Anti–IL-1β is complementary to the sequence in the 5′ upstream region of the IL-1β promoter. Its mediated inhibition of IL-1β production occurred at the transcriptional level. Anti–IL-1β did not alter the methylation status of the IL-1β promoter. However, chromatin immunoprecipitation assays revealed that the anti–IL-1β transcript can change the chromatin structure of the IL-1β promoter by decreasing H3K4 trimethylation on the promoter, which is at least part of the mechanism underlying the reduced binding of RNA polymerase II to the IL-1β promoter upon anti–IL-1β expression. Our data suggest that some antisense transcripts of innate immunity-related genes play a role by regulating cytokine expression.
B Lymphocyte “Original Sin” in the Bone Marrow Enhances Islet Autoreactivity in Type 1 Diabetes–Prone Nonobese Diabetic Mice
Authors: Henry-Bonami Rachel A. , Williams Jonathan M. , Rachakonda Amita B. , Karamali Mariam , Kendall Peggy L. , Thomas James W. 
Published: May 2013

Abstract
Effective central tolerance is required to control the large extent of autoreactivity normally present in the developing B cell repertoire. Insulin-reactive B cells are required for type 1 diabetes in the NOD mouse, because engineered mice lacking this population are protected from disease. The Cg-Tg(Igh-6/Igh-V125)2Jwt/JwtJ (VH125Tg) model is used to define this population, which is found with increased frequency in the periphery of NOD mice versus nonautoimmune C57BL/6 VH125Tg mice; however, the ontogeny of this disparity is unknown. To better understand the origins of these pernicious B cells, anti-insulin B cells were tracked during development in the polyclonal repertoire of VH125Tg mice. An increased proportion of insulin-binding B cells is apparent in NOD mice at the earliest point of Ag commitment in the bone marrow. Two predominant L chains were identified in B cells that bind heterologous insulin. Interestingly, Vκ4-57-1 polymorphisms that confer a CDR3 Pro-Pro motif enhance self-reactivity in VH125Tg/NOD mice. Despite binding circulating autoantigen in vivo, anti-insulin B cells transition from the parenchyma to the sinusoids in the bone marrow of NOD mice and enter the periphery unimpeded. Anti-insulin B cells expand at the site of autoimmune attack in the pancreas and correlate with increased numbers of IFN-γ–producing cells in the repertoire. These data identify the failure to cull autoreactive B cells in the bone marrow as the primary source of anti-insulin B cells in NOD mice and suggest that dysregulation of central tolerance permits their escape into the periphery to promote disease.
Sialyltransferase ST3Gal-III Regulates Siglec-F Ligand Formation and Eosinophilic Lung Inflammation in Mice
Authors: Suzukawa Maho , Miller Marina , Rosenthal Peter , Cho Jae Youn , Doherty Taylor A. , Varki Ajit , Broide David 
Published: May 2013

Abstract
Sialic acid–binding, Ig-like lectin (Siglec)-F is highly expressed on mouse eosinophils and plays an important role in regulating levels of eosinophilic lung inflammation. In this study we investigated the mechanism of constitutive and inducible Siglec-F ligand expression by lung airway epithelial cells and inflammatory cells in wild-type (WT) and genetically altered mice (ST3Gal-III heterozygotes, Fuc-TIV/VII double null, STAT6 null). Flow cytometry demonstrated that Siglec-F ligands are constitutively expressed in vitro and in vivo in selected lung cell types (epithelial cells, eosinophils, macrophages, and mast cells, but not CD4, CD8, or B cells) and are induced in response to divergent stimuli, including innate stimuli (TLR ligands, Alternaria), Th2 cytokines (IL-4, IL-13), and adaptive immune stimuli (OVA allergen). Furthermore, studies of deficient mice demonstrated the greater importance of the sialyltransferase ST3Gal-III compared with fucosyltransferases Fuc-TIV/VII in the synthesis of the constitutive and inducible Siglec-F ligands by lung epithelial and nonepithelial cells. In keeping with this, ST3Gal-III heterozygote mice (deficient in expression of Siglec-F ligands) also had significantly enhanced OVA-induced eosinophilic airway inflammation associated with reduced eosinophil apoptosis. Reduced eosinophil apoptosis in the lung of ST3Gal-III–deficient mice is likely mediated by reduced epithelial expression of Siglec-F ligands as WT eosinophils (which highly express Siglec-F) cultured with ST3Gal-III–deficient epithelial cells (which do not express Siglec-F ligand) showed reduced eosinophil apoptosis compared with WT eosinophils cultured with WT epithelial cells. Overall, these studies demonstrate that ST3Gal-III plays an important role in Siglec-F ligand formation and eosinophil apoptosis with resultant effects on eosinophilic inflammation in the lung.
The Effects of rhBMP-2 and Treg/Th17 Functional Disequilibrium in Uremic Patients with Cardiovascular Complication after Maintenance Hemodialysis
Authors: Danyan Chen , Xiaolong Huang , Song Lu , Hua Gan , Weixue Tang , Ke Liu 
Published: May 2013

Objectives We compared the correlation of regulatory T cell (Treg) and Th17 cell function disequilibrium with calcification in uremic patients on maintenance hemodialysis (MHD) with healthy controls, and investigated if their influence possibly increased the development and outcome of cardiovascular complications in uremic patients after MHD. Methods The extent of coronary artery calcification was assessed by coronary artery calcification scoring (CACS) in uremic patients with and without adverse cardiovascular events after MHD (MHD group 1 vs. MHD group 2, respectively). Peripheral blood mononuclear cells were incubated with rhBMP-2 as positive control. The Treg/Th17 cell frequencies, Foxp3 ROR-γt mRNA expressions, and MIP 3α/CCL20 concentrations were measured. Results The CACS score was significantly higher in MHD group 1 as compared group 2. In comparison with controls, rhBMP-2 upregulates Treg/Th17 functional disequilibrium in uremic patients, displayed higher Treg and Th17 frequencies, Foxp3 and ROR-γt expressions, and MIP3α/CCL20 concentrations. However, the up-regulations of Treg frequencies and Foxp3 expressions were significant in controls but not in MHD patients. It was also observed that Treg/Th17 functional disequilibrium was not only correlated with rhBMP-2 state but also consistent with the cardiovascular complications. Moreover, the CACS was negatively correlated with Treg cell frequencies but positively correlated with Th17 cell frequencies and MIP3α/CCL20 concentrations. Conclusions Function disequilibrium of Treg/Th17 was related to the degree of the rhBMP-2 state. Function disequilibrium of the Treg/Th17 might act synergistically with rhBMP-2 in the high incidence of immune-mediated cardiovascular complications after MHD.
Protein Synthesis in Neurons
Authors: Fallon Justin R , Taylor Aaron B 
Published: May 2013

Abstract

Neurons are immensely complex cells whose morphology and physiology underpin our cognition. Achieving proper neuronal connections during development, as well as eliciting appropriate responses to environmental stimuli in the adult, requires precisely regulated protein synthesis. To meet these requirements, neurons have adapted regulatory mechanisms that act at every step in the process of producing functional proteins. Many of these mechanisms target
messenger ribonucleic acid
(mRNA)‐binding proteins and ribosomal subunits to regulate translational initiation. These mechanisms are especially concentrated at synapses, where they act to transform transient electrical signals into lasting functional modifications that are a basis for learning and memory. Misregulated synaptic protein synthesis contributes to several human cognitive changes including addiction, fragile X syndrome and autism.

Key Concepts:

Neurons exhibit extensive and compartmentalised arbours of axons and dendrites, which place unique demands on the timing and location of protein synthesis.

Growth cones are specialised structures that guide developing axons and dendrites to their targets. Extracellular guidance cues regulate local protein synthesis in growth cones to guide axons and dendrites to their destination.

Forming new memories requires protein synthesis during specific time intervals after learning.

In the adult brain, neurons rapidly communicate through specialised contacts called synapses. The strength of communication at a synapse can be modified as a function of its past use. These changes are mediated, in part, by the local protein synthesis at the synapse.

Biochemical networks called signal transduction pathways convert specific patterns of synaptic transmissions into new protein synthesis. Ribosomal and RNA‐binding proteins are common targets of these pathways.

Alterations of neuronal protein synthesis in humans can cause a variety of behavioural, cognitive and memory deficits.
Antigenic Variation in Microbial Evasion of Immune Responses
Authors: Kotwal Girish J , Kulkarni Amod P 
Published: May 2013

Abstract

Antigenic variation is the means by which a number of highly pathogenic microorganisms, ranging from the electronmicroscopic human viruses to bacteria to fungi and unicellular protozoan parasites, passively evade immune surveillance. Through the understanding of the growing variety of mechanisms of the antigenic variation of surface proteins, it has become possible for us to determine what is preventing the host organism from mounting an effective immune response. Antigenic variation has serious public health consequences, for example, the current human immunodeficiency virus pandemic and the looming influenza pandemic, as well as a significant challenge to developing vaccines capable of eliciting long‐lasting or life‐long protective immunity against several pathogens.

Key Concepts:

Antigenic variation is a major mechanism of passively evading the host immune surveillance.

Antigenic variation is exhibited by a number of highly pathogenic microorganisms including human viruses, bacteria, fungi and unicellular protozoans.

Antigenic variation poses challenges to vaccine development against microorganisms causing major public health problems globally.

HIV‐1 surface glycoproteins display antigenic variation due to a high mutation rate during replication and significant tolerance of the variation.

Heterochromatin in the chromososome ends (telomers) in the malarial parasites mediate epigenetic regulation in the malaria parasite
Plasmodium falciparum
.

African trypanosomes control antigenic variation by periodically switching its variant surface glycoprotein involving transposition followed by recombination occurring at the telomeric expression site.

Targeting conserved regions of surface glycoproteins by using broadly neutralising antibodies against highly conserved exposed sites in surface proteins.

Targeting the oligosaccharides on surface glycoproteins, such as by the use of enveloped virus neutralising compounds (EVNCs).
Immunosuppression: Use in Transplantation
Authors: Suryavanshi Dilip , Prabhakaran Sangeetha , Matas Arthur J , Humar Abhinav 
Published: May 2013

Abstract

Clinical immunosuppression is the reduction of undesirable immunologic activity, usually achieved using immunosuppressive drugs. It is used in a variety of medical conditions, including inflammatory diseases and autoimmune disorders, but its most common application is in the field of organ transplantation. It has really been the advent of modern immunosuppression that has allowed for the growth and success of organ transplantation to the point where it now represents the standard treatment for many cases of end‐stage organ disease. The number of agents available for clinical use has increased significantly in the last two decades, with newer agents that more specifically target the involved portions of the immune system. Despite the advancements, however, the biggest challenge with immunosuppression remains the need to effectively balance immunosuppression to prevent rejection with the inherent toxicities associated with these medications.

Key Concepts:

Immunosuppressive therapy is a double‐edged sword; significant impact has been made on the prevention and treatment of rejection, but this has been associated with a significant increase in the risk of infections and certain types of malignancies.

Although steroids remain important immunusuprresive agents, because of their many side effects, recent efforts have focussed on how to minimise or avoid steroids completely.

Nephrotoxicity is the most important and troubling adverse effect of cyclosporine.

Tacrolimus is currently used widely worldwide in essentially all organ transplantation centres.

Adverse effects of tacrolimus and cyclosporine are similar, most commonly related to nephrotoxicity, neurotoxicity, impaired glucose metabolism, hypertension, infection and gastrointestinal disturbances.

Sirolimus and everolimus are not associated with the nephrotoxic side effects seen with the calcineurin inhibitors.

MMF is an antimetabolite and works to prevent proliferation of the stimulated T cell.

Antibody use, both polyclonal and monoclonal, has increased significantly in transplant.

Infection remains a major cause of morbidity and mortality after solid organ transplants.

Organ transplant recipients have an increased risk for developing certain types of
de novo
malignancies, including nonmelanomatous skin cancers, lymphoproliferative disease, gynaecologic and urologic cancers and Kaposi sarcoma.
Monoclonal Antibodies: Diagnostic Uses
Authors: Zola Heddy , Mohandas Arunesh Pullaniparambil , Krumbiegel Doreen 
Published: May 2013

AbstractDiagnosis of disease is a complex process requiring the clinician to deduce, from a set of symptoms and observations, an underlying cause, to predict which of the several therapeutic options is most likely to be effective, and to monitor that effectiveness. Laboratory tests that identify infectious agents, abnormal cells or elements of the body's response to disease, that quantify or localise particular molecules, cells or organisms in body fluids or tissues can provide valuable information to help the clinician with the initial diagnosis, with differential diagnosis (when the symptoms are consistent with several alternative causes) and with selection and monitoring of therapy. Antibodies, because of their exquisite specificity, are particularly useful reagents in this context, and monoclonal antibodies generally show superior specificity compared with polyclonal mixtures of antibodies. Monoclonal antibodies are used widely in the diagnosis of disease, whether in the diagnostic laboratory, in the doctor's rooms or in the field.Key Concepts:Correct diagnosis is a prerequisite to appropriate treatment of disease.Antibodies make useful reagents for identifying infectious or other disease‐causing agents.Monoclonal antibodies are particularly specific and often provide the best diagnostic reagents.Antibodies can be used in a variety of assay formats, designed to answer different questions – presence or absence of a particular substance, amount present and localisation within tissues.The rapid identification of new or rare infectious agents is an important public health measure, to monitor and reduce the chances of epidemics (as we see every few years with a new threat from an influenza variant).Disease often results from imbalances or defects in normal physiological mechanisms, especially the immune system. Many diagnostic tests therefore analyse the components of normal physiological processes.Laboratory tests are useful after the initial diagnosis, to monitor the effects of therapy.Diagnostic tests are generally done in a specialised diagnostic laboratory, but it is often advantageous to perform tests at ‘point of care’ or at home.
Selection and Complex Multigene Traits
Authors: Hasson Esteban R , Fanara Juan José , Frankel Nicolás 
Published: May 2013

AbstractPhenotypic characters that display continuous variation are usually called ‘quantitative traits’ or ‘complex traits’. Alternatively, geneticists refer to them as ‘multigene traits’, because the underlying genetic architecture is assumed to be polygenic. Analyses of the genetic architecture of diverse quantitative traits suggest that the number of loci (quantitative trait loci, QTLs) affecting trait variation can be very different. Moreover, experimental studies report contrasting genetic architectures, where either large‐effect QTLs or small‐effect QTLs explain most of the phenotypic variation. In addition, recent reports highlight the pervasiveness of epistasis. Considerable evidence, obtained with the QST–FST methodology, supports the idea that natural selection plays a key role in the evolution of complex traits. Nevertheless, the identification of a representative number of genes underlying QTLs is necessary to determine the contribution of selection, drift and gene flow for the evolution of complex traits.Key Concepts:The phenotypic variation in complex traits is usually determined by multiple genes.Understanding the genetic architecture of complex traits begins with the identification and characterisation of quantitative trait loci (QTLs).The search for the genes that harbour naturally segregating variation affecting quantitative traits is commonly performed through linkage QTL mapping.An analysis of the genetic architecture of different characters suggests that the number of QTLs contributing to a trait can be very different.Researchers aim to discover the genes (QTGs) and nucleotides (QTNs) underlying QTL effects.The comparison of the statistics of QST and FST is one of the most popular methods employed to search for the signature of natural selection on quantitative traits.Considerable evidence supports the idea that natural selection is a key player in the evolution of complex traits.The identification of a representative number of QTGs is necessary to determine the contributions of selection, drift and gene flow for the evolution of complex traits.
Gene Fusion
Authors: Williford Anna , Betrán Esther 
Published: May 2013

AbstractGene fusion is a process by which the complete or partial sequences of two or more distinct genes are fused into a single chimeric gene or transcript, as a result ofdeoxyribonucleic acid‐ orribonucleic acid‐derived rearrangements. This phenomenon is widespread and has been observed across all domains of life. Comparative genomics studies reveal high and persistent incidence of gene fusions and identify lineage‐specific factors that promote or hinder the formation of chimeric genes. Studies of recent gene fusions expose the mechanisms of their origin and the diversity of functional changes that accompany their formation. Gene fusions prominently contribute to evolutionary change by providing a continuous source of new genes. Gene duplications often precede gene fusions, permitting the evolution of chimeric genes, but at the same time preserving the original functions. Despite the reputation of gene fusions as drivers of adaptive evolution, gene fusions can have devastating consequences, often leading to genomic disorders or cancer.Key Concepts:Gene fusions form through DNA‐derived rearrangements or through transcription‐mediated mechanisms (novelcis‐ ortrans‐splicing).Gene or domain duplications often precede gene fusions preserving the original functions of parental genes and therefore facilitating the evolution of new functions by chimeric gene products.Young gene fusions (polymorphic or recently fixed) retain molecular signatures of their formations revealing the mechanisms of origin.The formation of chimeric genes generally involves two steps: juxtaposition of the sequences involved in fusion and subsequent mutations that generate a single chimeric transcriptional unit under the control of a single regulatory system.Various replicative (i.e. replication related) and nonreplicative mechanisms of DNA break repair can result in gene duplication and gene movement.Transposable elements greatly facilitate gene fusions by (1) mediating gene duplication and gene movements, (2) providing the source of reverse transcriptase required for retropositions and (3) directly participating in gene fusions.Gene fusion often generates a novel product with functional capabilities distinct from those of its parental genes, ensuring frequent contribution of chimeric genes to adaptive evolution.Gene fusions in the germline can lead to genomic disorders, whereas gene fusions in somatic cells are associated with many different cancers, frequently as mutations that initiate tumourigenesis.