bluuebunny/crossref_metadata_2025 huggingface dataset:
Translational Readthrough of Premature Termination Codons in a Therapeutic Context
Authors: Bidou Laure , Sandra Blanchet , Olivier Namy
Published: February 2016

Coding sequences are defined between a start and a stop codon. The appearance of a nonsense mutation in a coding sequence creates a premature termination codon (PTC), preventing the correct production of the corresponding protein by interrupting translation and inducing the degradation of the transcript via the nonsense‐mediated mRNA decay (NMD) pathway. Over the past 10 years, there has been considerable interest in the possibility of suppressing in‐frame PTCs for therapeutic purposes. Indeed, some drugs have been shown to promote PTC readthrough by binding to mammalian ribosomes, thereby partially restoring the synthesis of a full‐length protein in cultured mammalian cells and animal models. This translational suppression strategy represents a promising therapeutic approach for genetic diseases and cancers due to a PTC.

Key Concepts

The stop codons in humans are UAA, UAG and UGA, and they are recognised by release factors.

Near‐cognate tRNA‐binding codons display base pairing for only two of the three bases of the codon.

Stop codon readthrough is the process by which the ribosome incorporates a near‐cognate tRNA at the stop codon.
Monogenic Autoinflammatory Diseases
Authors: Verbsky James , Gallagher Joel
Published: February 2016

Defects in the immune system that result in spontaneous inflammation are termed autoinflammatory disorders. In contrast to autoimmune diseases, they are not mediated by autoantibodies or autoreactive lymphocytes. Prominent features include fevers and rash, although other symptoms are observed. Flares are typically episodic and vary in severity, but do not worsen over time as in autoimmune disorders. Recent improvements in genetic technologies have led to the characterisation of multiple autoinflammatory syndromes. Prior to understanding the underlying mechanisms, these were treated with systemic anti‐inflammatory medications such as NSAIDs or glucocorticoids, which have adverse side effects. Advances in understanding the underlying etiologies have led to the discovery of novel options for targeted treatments.

Key Concepts

Autoinflammatory syndromes are characterised by fevers, rash, arthritis, myalgias and various other symptoms, although each syndrome may not present with all of these.

Autoinflammatory syndromes are related to the innate arm rather than the adaptive arm of the immune system.

The autoinflammatory syndromes typically first present in childhood.

The inflammasome and interleukin 1 (IL‐1) are key mediators in many autoinflammatory syndromes.

Genetic testing provides a definitive diagnosis of the underlying etiology of autoinflammatory syndromes.

Understanding the various pathways of autoinflammatory syndromes provides multiple targets of novel treatment modalities.
Local Adaptation in Plants
Authors: Lascoux Martin , Glémin Sylvain , Savolainen Outi
Published: February 2016

Local adaptation reflects the fact that local populations tend to have a higher mean fitness in their native environment than in other environments and in other populations introduced in their home site. Starting in the 1920s a large number of reciprocal transplant and common garden experiments, as well as studies of populations along environmental clines, have demonstrated that local adaptation is widespread in plants. One remaining challenge is to understand how populations become locally adapted and to characterise the genes involved in this process. Theoretically, local selection at single loci will promote local adaptation and gene flow will decrease it. For quantitative traits, the situation is more complex, and strong local adaptation can even be established and maintained in the presence of higher gene flow. The genetic basis of local adaptation will evolve through time, and eventually trade‐offs between alleles at a locus may occur in the different environments (antagonistic pleiotropy).

Key Concepts

Local adaptation is widespread in plants but its genetic basis is still poorly known.

Local adaptation is the property of a group of populations in a given set of environments.

Local adaptation depends primarily on the balance between selection and migration.

The genetic architecture of local adaptation, in particular the presence of trade‐offs, is likely to be variable among species as it will depend, among other things, on the time since the populations diverged or the amount of gene flow between them.
Computational Prediction of Genetic Drivers in Cancer
Authors: Djotsa Nono Alice B , Chen Ken , Liu Xiaoming
Published: February 2016

Cancer is a complex genetic disease driven by somatic mutations in the genomes of cancer cells. Distinguishing pathogenic ‘driver’ mutations from non‐pathogenic ‘passenger’ mutations is a central task for functionalising cancer genomics in patient care. With the outpouring of genomic information from next‐generation sequencing, predictive algorithms have become relevant to filter the outnumbered pathogenic driver mutations from non‐pathogenic passenger mutations. Computational approaches are available for predicting cancer drivers at mutation, gene and pathway levels. These algorithms use statistical approaches that have their advantages and drawbacks. The current trend is to use multiple and complementary methods for a more accurate prioritisation of cancer driver candidates available for targeted therapy at the clinical level.

Key Concepts

Cancer is a disease driven by mutations in the genome.

Only a small fraction of mutations are drivers that are responsible for cancer initiation and progression.

Distinguishing drivers from passengers is essential for genomic medicine.

Computational prediction of drivers is challenging due to the complexity of biology and genomics.

Statistical and machine learning approaches have been applied to discover the signature of drivers.

A mutation can affect the function of multiple genes and pathways.

The function of a mutation is context‐dependent and can vary in different diseases.
Ecological Insights from Ancient
DNA
Authors: Brown Sarah K , Blois Jessica L
Published: February 2016

Species have been shaped by past environmental conditions. Ancient remnants of species (bones, teeth, coprolites, pollen, shed cells, etc.) with preserved DNA (deoxyribonucleic acid) can reveal responses to past environmental changes through genetic information in the form of ancient DNA. Here we review the uses of ancient DNA to gain insights into ecological and evolutionary processes by investigating: (1) how climate has affected population dynamics through time, (2) how species react differently to climate change, (3) what triggers extinction for some species, (4) the detection of genomic adaptation to the environment and (5) how ancient DNA can be used to reconstruct past environmental conditions/habitats. The details that we can glean from past responses to climate change will provide information on how we can expect species to respond to future climate change.

Key Concepts

Ancient DNA (aDNA) can be utilised to infer how species reacted to past ecological changes.

Populations are dynamic and respond to past climate change in many ways; through population size change, altered distributions and migrations.

In combination with environmental data, ancient DNA is helping to elucidate what drove some species to extinction.

Species have adapted to past climates. Ancient DNA, primarily through candidate gene searches, has revealed the genes behind these adaptations.

Indirect methods of sampling soil for ancient DNA has aided in reconstructing past habitats.

Ancient DNA can decipher how species responded to past natural climate change. This information can be used to aid in conservation.
Higher Order Genetic Interactions and Complex Trait Variation
Authors: Matsui Takeshi , Ehrenreich Ian M
Published: February 2016

Genetic variants that segregate within species can cause individuals to show heritable phenotypic differences. Some of these polymorphisms act the same regardless of the other variants with which they co‐occur. However, many of these polymorphisms exhibit genetic (or epistatic) interactions with each other and thus show different effects across genetic backgrounds. These interactions represent a potentially important source of heritable trait variation, but are difficult to identify in most genetic mapping studies. For this reason, researchers typically focus on two‐locus interactions, which are the least complex and easiest to identify form of interaction. Although two‐locus interactions are undoubtedly important, higher order genetic interactions (HGIs) involving three or more loci can also occur. In this article, we discuss the phenotypic effects, underlying molecular mechanisms and potential biological significance of these HGIs.

Key Concepts

Higher order genetic interactions (HGIs) occur when three or more polymorphisms collectively exhibit unexpected phenotypic effects.

Detecting HGIs is difficult, especially as the number of involved loci increases.

Evidence suggests that genetically complex perturbation of gene regulatory networks might be the major source of HGIs.

HGIs can cause individuals to show different susceptibilities to environmental change and mutation.
Therapeutic Applications of
RNA
Interference
Authors: Deng Yan , Chen Jiao , Zhao Yi , Tang Tao
Published: February 2016

During recent decades there have been remarkable advances in biology, in which one of the most important discoveries is ribonucleic acid interference (RNAi). RNAi is a specific post‐transcriptional regulatory pathway that can result in silencing gene functions. RNAi products include small interfering ribonucleic acid (siRNA) and also short hairpin ribonucleic acid (shRNA), microRNA (miRNA) and Piwi‐interacting ribonucleic acid (piRNA). They combine with homologous fragments of the mRNA (messenger ribonucleic acid) and cause its degradation. It results in inhibition of protein synthesis, or in mutation in the gene encoding it. Efforts have been taken to translate this new discovery into clinical applications for disease treatment. The basic and clinical research has been focused on the following targets: cancer, cardiovascular diseases, neurodegenerative diseases, virus‐related diseases as well as skin disorder and ocular disorders.

Key Concepts

RNA interference (RNAi) is a specific post‐transcriptional gene‐silencing mediated by small RNAs.

RNA‐induced silencing complex (RISC) is important for RNAi.

RNAi has become a potential treatment for human diseases.

RNAi can inhibit tumour cell growth, angiogenesis, metastasis and chemoresistance.

RNAi suppresses disease‐linked genes and has a potential for the treatment of cardiovascular neurodegenerative and virus‐related diseases.
Subcellular Protein Localisation in Health and Disease
Authors: Florindo Claudia , Ferreira Bibiana I , Serrão Sónia M , Tavares Álvaro A , Link Wolfgang
Published: February 2016

The nonhomogeneous distribution of cellular components is an essential property of all cells. Macromolecules are generally not capable of freely diffusing throughout the cell. In addition, the eukaryotic cell is organised into membrane‐covered compartments that are characterised by different metabolic activities and specific proteins. The synthesis of proteins is confined to only one of these compartments, the cell cytosol. As proteins exert their functions in different organelles of the cell, protein translocation is a fundamental requirement of cell physiology. The asymmetry of cellular constituents is essential for cellular signalling and their aberrant localisation contributes to the pathogenesis in many human diseases. In this article, we provide an overview of mechanisms involved in physiological and pathological protein translocations. We provide examples for experimental procedure to investigate these mechanisms and discuss strategies to interfere with protein translocation mechanisms to treat diseases.

Key Concepts

In order to exert their function, proteins have to be at the right place at the right time.

The eukaryotic cell is a very crowded environment with many diffusion barriers.

Sophisticated mechanisms of protein trafficking to ensure accurate subcellular protein localisation have evolved.

Accurate protein trafficking can fail due to alterations such as mutations and post‐translational modifications at different levels of the transport pathways.

The resulting protein mislocalisation can lead to a broad variety of human diseases.

Significant technological progress has been made, allowing for unprecedented possibilities to monitor subcellular protein localisation.

Two therapeutic strategies to target protein localisation have emerged: Therapeutic restoration of physiological protein localisation and therapeutic mistargeting to inactivate disease‐causing proteins.
Genetic Modifiers in
H
untington Disease
Authors: Clabough Erin BD , Thompson Jefferson C , Lau James H , Savarese Melchior F , Harris Evan C , Manos Sean T , Kyle Charles T , Meinhardt John T , Sheffield John W , Boudin Michael D , Abdi Myshake S , Mohay John AS , Harriss Robert W , Luck Mason E , Owens Alan M , Britt John W
Published: February 2016

Huntington disease (HD) is a neurodegenerative disorder that is caused by an elongation of a normally occurring polyglutamine stretch within the huntingtin (HTT) protein. Since the mutation was first identified, multiple HD‐disease‐modifying gene candidates that can hasten or delay age of onset (AO) have been discovered. For the past several decades, candidate disease‐modifying genes have been chosen for investigation based on functionality or prior implication in the disease process. More recent approaches take advantage of newly available genomic‐wide assays to identify changes as small as single‐nucleotide polymorphisms (SNPs) in other parts of the genome. New information regarding disease‐modifying genes will continue to elucidate potential HD therapeutic candidates.

Key Concepts

Huntington disease is a neurodegenerative disease that results from excess CAG trinucleotide repeats in exon 1 of the
HD
gene, which is located in chromosome 4p16.3 and encodes the HTT protein.

The number of CAG repeats in the
HD
gene inversely affects the age of onset (AO) in HD patients.

Genetic modifiers are identified genes that have the ability to either hasten or delay AO of HD; however, the exact mechanism of many of these genes in association with the disease is unknown.

HD genetic modifiers can significantly delay specific physiological HD symptoms, such as chorea.

Some HD genetic modifiers can alter HD AO by up to 8 years.

Genetic modifiers have been discovered by either the candidate approach, which involves exploring genes known to be associated with the HTT protein and genotyping any variants, or via a more unbiased genomic approach, which involves a broad search for genes that are not known to be associated with the HTT protein.

Modifiers that affect HD do not necessarily need to be within close vicinity of the actual gene, but can be distributed elsewhere in the genome, even in noncoding regions.
Men's harassment behavior in online video games: Personality traits and game factors
Authors: Tang Wai Yen , Fox Jesse
Published: February 2016

Online video games afford co‐play and social interaction, often anonymous, among players from around the world. As predicted by the social identity model of deindividuation effects, undesirable behavior is not uncommon in online gaming environments, and online harassment has become a pervasive issue in the gaming community. In this study, we sought to determine what personality traits and game‐related variables predicted two types of online aggression in video games: general harassment (e.g., skill‐based taunting, insulting others’ intelligence) and sexual harassment (e.g., sexist comments, rape threats). Men who play online video games (N = 425) participated in an anonymous online survey. Social dominance orientation and hostile sexism predicted higher levels of both sexual harassment and general harassment in online games. Game involvement and hours of weekly gameplay were additional predictors of general harassment. We discuss implications of online social aggression and online sexual harassment for online gaming. We also apply our findings to the broader understanding of online harassment, cyberaggression, cyberbullying, and other forms of online hostility in computer‐mediated communication contexts. Aggr. Behav. 42:513–521, 2016. © 2016 Wiley Periodicals, Inc.
Long‐Term Effects of Glucosamine and Chondroitin Sulfate on the Progression of Structural Changes in Knee Osteoarthritis: Six‐Year Followup Data From the Osteoarthritis Initiative
Authors: Raynauld Jean‐Pierre , Pelletier Jean‐Pierre , Abram François , Dodin Pierre , Delorme Philippe , Martel‐Pelletier Johanne
Published: February 2016

Objective

To examine the long‐term (6‐year) effect of combined glucosamine (Glu) and chondroitin sulfate (CS) treatment on cartilage volume in knee osteoarthritis (OA).

Methods

Participants were from the Osteoarthritis Initiative progression and incidence subcohorts, had magnetic resonance imaging (MRI) of the target knee at baseline and 6 years, joint space width >1 mm, and data available on Glu/CS consumption (n = 1,593). They were stratified into 2 main groups based on whether or not they had medial meniscal extrusion at baseline. The group with meniscal extrusion (n = 429) was further stratified into subgroups based on exposure or no exposure to Glu/CS as follows: not exposed, 1 year, 2–3 years, and 4–6 years. Cartilage volume was assessed using fully automated quantitative MRI technology.

Results

The Jonckheere‐Terpstra trend test indicated that treatment with Glu/CS significantly reduced the cartilage volume loss in the global knee, associated with the lateral compartment. Multivariate analysis further demonstrated that the extent of the treatment's positive effect was related to exposure time to treatment, the protective effect at 6 years being significant in participants exposed to ≥2 years of treatment.

Conclusion

These findings provide future support for the long‐term protective structure‐modifying effects of Glu/CS treatment in knee OA subjects.
Defining an International Standard Set of Outcome Measures for Patients With Hip or Knee Osteoarthritis: Consensus of the International Consortium for Health Outcomes Measurement Hip and Knee Osteoarthritis Working Group
Authors: Rolfson Ola , Wissig Stephanie , van Maasakkers Lisa , Stowell Caleb , Ackerman Ilana , Ayers David , Barber Thomas , Benzakour Thami , Bozic Kevin , Budhiparama Nicolaas , Caillouette James , Conaghan Philip G. , Dahlberg Leif , Dunn Jennifer , Grady‐Benson John , Ibrahim Said A. , Lewis Sally , Malchau Henrik , Manzary Mojieb , March Lyn , Nassif Nader , Nelissen Rob , Smith Noel , Franklin Patricia D.
Published: February 2016

Objective

To define a minimum Standard Set of outcome measures and case‐mix factors for monitoring, comparing, and improving health care for patients with clinically diagnosed hip or knee osteoarthritis (OA), with a focus on defining the outcomes that matter most to patients.

Methods

An international working group of patients, arthroplasty register experts, orthopedic surgeons, primary care physicians, rheumatologists, and physiotherapists representing 10 countries was assembled to review existing literature and practices for assessing outcomes of pharmacologic and nonpharmacologic OA therapies, including surgery. A series of 8 teleconferences, incorporating a modified Delphi process, were held to reach consensus.

Results

The working group reached consensus on a concise set of outcome measures to evaluate patients’ joint pain, physical functioning, health‐related quality of life, work status, mortality, reoperations, readmissions, and overall satisfaction with treatment result. To support analysis of these outcome measures, pertinent baseline characteristics and risk factor metrics were defined. Annual outcome measurement is recommended for all patients.

Conclusion

We have defined a Standard Set of outcome measures for monitoring the care of people with clinically diagnosed hip or knee OA that is appropriate for use across all treatment and care settings. We believe this Standard Set provides meaningful, comparable, and easy to interpret measures ready to implement in clinics and/or registries globally. We view this set as an initial step that, when combined with cost data, will facilitate value‐based health care improvements in the treatment of hip and knee OA.
Continuous Improvement of Physical Functioning in Ankylosing Spondylitis Patients by Tumor Necrosis Factor Inhibitors: Three‐Year Followup and Predictors
Authors: van Weely Salima F. E. , Kneepkens Eva L. , Nurmohamed Mike T. , Dekker Joost , van der Horst‐Bruinsma Irene E.
Published: February 2016

Objective

To establish the 3‐year outcome and course of physical functioning and spinal mobility impairments in patients routinely treated with tumor necrosis factor inhibitors (TNFi) and to find predictors of physical functioning and spinal mobility impairments.

Methods

Ankylosing spondylitis (AS) patients eligible for TNFi were followed in a 3‐year prospective observational study. Prediction models were developed with linear mixed modeling. Bath Ankylosing Spondylitis Functional Index (BASFI) and Bath Ankylosing Spondylitis Metrology Index (BASMI) were used as outcome measures for physical functioning and spinal mobility.

Results

A total of 257 patients were included and treated with etanercept (n = 174) or adalimumab (n = 83). Physical functioning improved significantly during the first 6 months after the start of TNFi. The BASFI score decreased from mean ± SD 5.4 ± 2.4 to 3.3 ± 2.6 at 6 months, and stabilized thereafter (BASFI third year score mean ± SD 3.6 ± 2.5). The BASMI showed no significant changes over time. Lower baseline BASFI and BASMI scores predicted a better level of physical functioning and spinal mobility after 3 years of TNFi therapy. Other predictors for a better 3‐year outcome and course of physical functioning included absence of comorbidity, physical activity, younger age, and lower body mass index at baseline.

Conclusion

Physical functioning in routinely TNFi‐treated AS patients improved up to 6 months and stabilized thereafter. Therefore, it would be better to extend the period of evaluation of TNFi treatment to 6 months rather than the 3 months currently used. The risk factors of long‐term physical functioning found in this study might help to identify patients at risk at an earlier stage and improve treatment strategy.
Robust output tracking of uncertain nonlinear systems with completely unknown dead‐zone input: A self‐tuning design approach
Authors: Wu Hansheng
Published: February 2016

The main purpose of this paper is to propose a direct and simple approach, called a self‐tuning design approach, to dealing with any nonsymmetric dead‐zone input nonlinearity where its information is completely unknown. In order to describe the approach, the output tracking problem is considered for a class of uncertain nonlinear systems with any nonsymmetric dead‐zone input. First, a dead‐zone input is represented as a time‐varying input‐dependent function such that the considered dynamical system with dead‐zone input can be transfered into an uncertain nonlinear dynamical system subject to a linear input with time‐varying input coefficient. Then, by making use of the self‐tuning design approach, a class of adaptive robust output tracking control schemes with a rather simple structure is synthesized. Thus, the proposed direct and simple self‐tuning design approach can be easily understood by the engineering designers, and the resulting simple adaptive robust control schemes can be well implemented in most practical engineering control problems. By combining the proposed self‐tuning design approach with other control methods, one may expect to obtain a number of interesting results for a rather large class of uncertain nonlinear dynamical systems with dead‐zone in the actuators. Finally,the simulations of some numerical examples are provided to demonstrate the validity of the theoretical results. Copyright © 2016 John Wiley & Sons, Ltd.
Electrically Conductive Silver Nanoparticles‐Filled Nanocomposite Materials as Surface Coatings of Composite Structures
Authors: Dermanaki Farahani Rouhollah , Gagne Martin , Klemberg‐Sapieha Jolanta E. , Therriault Daniel
Published: February 2016

Silver nanoparticles‐filled nanocomposite materials are fabricated and used as electrically conductive coatings for aerospace composite structures. Silver nanoparticles are first synthesized, then mixed with polymer solutions, and applied onto the surface of carbon fiber composite substrates either by casting or spraying technique. Two design strategies are studied: the reduction of nanofillers contact resistance using a conductive polymer as binder and the addition of a second polymer to fabricate a ternary biphasic nanocomposite for the further improvement of mechanical resistance of the coatings. The coatings are then annealed at different temperatures up to 200 °C and characterized using various techniques in order to evaluate their morphology, electrical resistivity, and mechanical performance. The thermal annealing considerably improves the adhesion of the coatings to the composite substrates as well as the scratch resistance of the coatings. A significant improvement (approx. six orders) of electrical properties is achieved for a ≈10 μm‐thick coating film after the thermal annealing. The best results are achieved with silver nanoparticles mixed with the conductive polymer binder with the maximum resistivity of 4.2 × 10−3 Ω g cm−2. The conductivity achieved here is fairly close to that values required in order for the materials to be used for coating of composite structures in potential aerospace applications such as electromagnetic interference shielding and lighting strike protection.
Adult neurogenesis and neurodegenerative diseases: A systems biology perspective
Authors: Horgusluoglu Emrin , Nudelman Kelly , Nho Kwangsik , Saykin Andrew J.
Published: February 2016

New neurons are generated throughout adulthood in two regions of the brain, the olfactory bulb and dentate gyrus of the hippocampus, and are incorporated into the hippocampal network circuitry; disruption of this process has been postulated to contribute to neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. Known modulators of adult neurogenesis include signal transduction pathways, the vascular and immune systems, metabolic factors, and epigenetic regulation. Multiple intrinsic and extrinsic factors such as neurotrophic factors, transcription factors, and cell cycle regulators control neural stem cell proliferation, maintenance in the adult neurogenic niche, and differentiation into mature neurons; these factors act in networks of signaling molecules that influence each other during construction and maintenance of neural circuits, and in turn contribute to learning and memory. The immune system and vascular system are necessary for neuronal formation and neural stem cell fate determination. Inflammatory cytokines regulate adult neurogenesis in response to immune system activation, whereas the vasculature regulates the neural stem cell niche. Vasculature, immune/support cell populations (microglia/astrocytes), adhesion molecules, growth factors, and the extracellular matrix also provide a homing environment for neural stem cells. Epigenetic changes during hippocampal neurogenesis also impact memory and learning. Some genetic variations in neurogenesis related genes may play important roles in the alteration of neural stem cells differentiation into new born neurons during adult neurogenesis, with important therapeutic implications. In this review, we discuss mechanisms of and interactions between these modulators of adult neurogenesis, as well as implications for neurodegenerative disease and current therapeutic research. © 2016 Wiley Periodicals, Inc.
Palladium‐Catalyzed Carbonylative Multicomponent Synthesis of Functionalized Benzimidazothiazoles
Authors: Veltri Lucia , Grasso Giuseppe , Rizzi Rosanna , Mancuso Raffaella , Gabriele Bartolo
Published: February 2016

The reactivity of 2‐(prop‐2‐ynylthio)‐1 H‐benzo[d]imidazoles and their corresponding hydrobromide salts under PdI2/KI‐catalyzed oxidative aminocarbonylation conditions has been studied. It is found that 2‐prop‐2‐ynylsulfanyl‐3 H‐benzimidazolium salts, when allowed to react with amines, carbon monoxide, and oxygen, under the catalytic action of PdI2 (1 mol %) in conjunction with KI (1 equiv), under suitable conditions (80 °C and 20 atm of a 4:1 mixture of CO/air, in MeCN, and in the presence of a six‐fold excess of amine, for 15 h), could be selectively converted into 2‐benzo[4,5]imidazo[2,1‐b]thiazol‐3‐yl‐N,N‐dialkylacetamides in 60–78 % yields, through an oxidative aminocarbonylation/heterocyclization process. The structure of a representative product, 2‐benzo[4,5]imidazo[2,1‐b]thiazol‐3‐yl‐1‐pyrrolidin‐1‐ylethanone, was confirmed by X‐ray diffraction analysis.
Palladium‐Catalyzed Direct Arylation of Azulene Based on Regioselective C−H Bond Activation
Authors: Murai Masahito , Yanagawa Mayu , Nakamura Masahiro , Takai Kazuhiko
Published: February 2016

An efficient synthesis of arylazulenes involving minimal steps was developed. The combination of Pd(OAc)2/XPhos as a catalyst and pivalic acid as an additive was key for the direct arylation of C−H bonds, and the reaction proceeded preferentially at the 1‐ and 3‐positions of azulene, without heteroatom‐containing directing groups. Compared with the traditional cross‐coupling protocol, the arylation method described here requires fewer steps and uses commercially available synthetic blocks. The degree of conjugation and the optical properties of the resulting azulene conjugates can be adjusted by simple protonation, which allows the current method to be an efficient strategy for exploiting novel azulene‐based functional materials.
Cadaveric validation study of computational fluid dynamics model of sinus irrigations before and after sinus surgery
Authors: Craig John R. , Zhao Kai , Doan Ngoc , Khalili Sammy , Lee John Y.K. , Adappa Nithin D. , Palmer James N.
Published: February 2016

Background

Investigations into the distribution of sinus irrigations have been limited by labor‐intensive methodologies that do not capture the full dynamics of irrigation flow. The purpose of this study was to validate the accuracy of a computational fluid dynamics (CFD) model for sinonasal irrigations through a cadaveric experiment.

Methods

Endoscopic sinus surgery was performed on 2 fresh cadavers to open all 8 sinuses, including a Draf III procedure for cadaver 1, and Draf IIb frontal sinusotomies for cadaver 2. Computed tomography maxillofacial scans were obtained preoperatively and postoperatively, from which CFD models were created. Blue‐dyed saline in a 240‐mL squeeze bottle was used to irrigate cadaver sinuses at 60 mL/second (120 mL per side, over 2 seconds). These parameters were replicated in CFD simulations. Endoscopes were placed through trephinations drilled through the anterior walls of the maxillary and frontal sinuses, and sphenoid roofs. Irrigation flow into the maxillary, frontal, and sphenoid sinuses was graded both ipsilateral and contralateral to the side of nasal irrigation, and then compared with the CFD simulations.

Results

In both cadavers, preoperative and postoperative irrigation flow into maxillary, frontal, and sphenoid sinuses matched extremely well when comparing the CFD models and cadaver endoscopic videos. For cadaver 1, there was 100% concordance between the CFD model and cadaver videos, and 83% concordance for cadaver 2.

Conclusion

This cadaveric experiment provided potential validation of the CFD model for simulating saline irrigation flow into the maxillary, frontal, and sphenoid sinuses before and after sinus surgery.
Characterization of immunoglobulin E plasma cells that are elevated in the upper airway mucosa of nonatopic patients with chronic rhinosinusitis without nasal polyps
Authors: Rashan Ali R. , Goshn Eliver , Peterson Asa , Yang Yang , Phillips Meghan , Sahaf Bita , Herzenberg Leonore , Nayak Jayakar V.
Published: February 2016

Background

The immunologic mechanisms driving inflammation in the upper airways of patients with chronic rhinosinusitis (CRS) are poorly understood. Previous studies have shown that B cells and immunoglobulin E (IgE) levels are elevated in the nasal tissue of patients with atopic chronic rhinosinusitis without nasal polyps (CRSsNP). However, less is known regarding B cell subsets and IgE‐producing plasmablasts in nonatopic CRSsNP patients.

Methods

Human blood and ethmoid sinus mucosa samples were analyzed from control (n = 6) and nonatopic CRSsNP (n = 11) patients. Tissue samples were evaluated using high‐dimensional flow cytometry.

Results

A population of IgE antibody secreting cells is significantly increased in situ within inflamed nasal tissue of nonatopic CRSsNP subjects when compared to control nasal tissue and the circulating peripheral blood (p < 0.05). This IgE plasma cell population displays ∼90% cell surface Ig lambda light chain, is mitotically active (Ki‐67+), and displays intracellular IgE expression. The predominant B cell population expressing IgE are plasmablasts (CD38high, CD138−) not typically found in the blood or peripheral tissue of these patients.

Conclusion

The nasal mucosa from nonatopic CRSsNP patients demonstrate a significant regional spike in resident in situ IgE plasmablast cells not seen in control nasal tissue or peripheral blood from the same patient. The restricted expression of Ig lambda light chain in this mitotically active IgE plasmablast population supports the hypothesis of aberrant B cell proliferation in the context of CRS. These findings suggest the presence of a unique regional immune microenvironment for B cell priming and/or selection within chronically inflamed airway tissues.
Safety analysis of long‐term budesonide nasal irrigations in patients with chronic rhinosinusitis post endoscopic sinus surgery
Authors: Soudry Ethan , Wang Jane , Vaezeafshar Reza , Katznelson Laurence , Hwang Peter H.
Published: February 2016

Background

Although the safety of topical nasal steroids is well established for nasal spray forms, data regarding the safety of steroid irrigations is limited. We studied the effect of long‐term budesonide nasal irrigations (>6 months) on hypothalamic‐pituitary‐adrenal axis (HPAA) function and intraocular pressure (IOP) in patients post–endoscopic sinus surgery.

Methods

This was retrospective case series. Adrenal function was assessed by using the high‐dose cosyntropin stimulation test.

Results

A total of 48 patients were assessed, with a mean duration of budesonide irrigations of 22 months. Stimulated cortisol levels were abnormally low in 11 patients (23%). None reported to have symptoms of adrenal suppression. Three of 4 patients who repeated the study being off budesonide for at least 1 month returned to near normal levels. Logistic regression analysis revealed that concomitant use of both nasal steroid sprays and pulmonary steroid inhalers was significantly associated with HPAA suppression (p = 0.024). Patients with low stimulated cortisol levels were able to continue budesonide irrigations under the supervision of an endocrinologist without frank clinical manifestations of adrenal insufficiency. IOP was within normal limits in all patients.

Conclusion

Long‐term use of budesonide nasal irrigations is generally safe, but asymptomatic HPAA suppression may occur in selected patients. Concomitant use of both nasal steroid sprays and pulmonary steroid inhalers while using daily budesonide nasal irrigations is associated with an increased risk. Rhinologists should be alerted to the potential risks of long‐term use of budesonide nasal irrigations, and monitoring for HPAA suppression may be warranted in patients receiving long‐term budesonide irrigation therapy.
The importance of mold sensitivity in nonallergic rhinitis patients
Authors: Demirtürk Mustafa , Gelincik Aslı , Ulusan Murat , Ertek Belkıs , Büyüköztürk Suna , Çolakoğlu Bahattin
Published: February 2016

Background

In recent studies, local specific immunoglobulin E (sIgE) production against allergens in nasal mucosa and a positive response to a nasal allergen provocation test (NAPT) have been demonstrated in some patients initially diagnosed as nonallergic rhinitis (NAR) or idiopathic rhinitis (IR). The aim of this study was to evaluate the presence of local allergic rhinitis (LAR) in patients who experience rhinitis symptoms in indoor and outdoor moldy conditions and to investigate the role of the NAPT in diagnosis.

Methods

A total of 40 NAR patients with a history of persistent rhinitis and who had negative skin‐prick tests (SPTs) and serum sIgE levels to common aeroallergens, as well as 20 healthy subjects were included in the study. NAPTs were performed with Aspergillus fumigatus (group 1) or a mixture of Alternaria alternata and Cladosporium herbarum extracts (group 2).

Results

In patient nasal lavage fluids, tryptase and mold sIgE levels were not significantly different from the control group. NAPT with Aspergillus fumigatus was positive in 8 of 12 NAR patients (66.6%) in group 1 and NAPT with the mixture of extracts was positive in 9 of 13 NAR patients (69.2%) in group 2.

Conclusion

This study suggests that LAR may exist in a significant number of the persistent rhinitis patients who were previously considered as NAR based on negative SPTs or serum sIgE tests. To the best of our knowledge, this is the first study evaluating a nasal local allergic response to both indoor and outdoor molds.
Canine Staphylococcus pseudintermedius sinonasal infection in human hosts
Authors: Kuan Edward C. , Yoon Alexander J. , Vijayan Tara , Humphries Romney M. , Suh Jeffrey D.
Published: February 2016

Background

Staphylococcus pseudintermedius is a gram‐positive bacterium commonly found as part of the normal skin and nasal flora of healthy dogs. It may act as an opportunistic pathogen in dogs, but has also been shown to colonize the nasal mucosa of humans. We report 4 cases of chronic rhinosinusitis (CRS) refractory to aggressive medical management with cultures that grew S. pseudintermedius, with clinical improvement only after initiating culture‐directed therapy.

Methods

Retrospective review of 4 patients with CRS treated at a tertiary academic medical center with sinonasal cultures growing S. pseudintermedius.

Results

All 4 patients are dog owners and had clinical diagnoses of CRS. Three of the 4 patients had a diagnosis related to immune dysfunction (sarcoidosis, Crohn's disease, history of lymphoma). After undergoing endoscopic sinus surgery, each patient was treated with aggressive medical therapy but continued to have purulent nasal discharge. Sinonasal cultures repeatedly grew S. pseudintermedius in all cases, with 3 patients’ dogs also having had concurrent S. pseudintermedius wound infections of the ear and leg with similar antibiotic susceptibilities. Treatment with culture‐directed therapy improved the infections in all cases.

Conclusion

Opportunistic pathogens have a propensity to exacerbate infection in CRS patients with immune dysfunction. We report the first case series of sinonasal S. pseudintermedius infection in humans. Though a rare cause of disease, pathogens such as S. pseudintermedius from nonhuman hosts should be considered in the management of CRS patients refractory to medical therapy.
Milde Cobalt‐katalysierte Negishi‐Kreuzkupplungen von (Hetero‐)Arylzinkreagentien mit (Hetero‐)Arylhalogeniden
Authors: Haas Diana , Hammann Jeffrey M. , Lutter Ferdinand H. , Knochel Paul
Published: February 2016

Ein katalytisches System bestehend aus 5 Mol‐% CoCl2⋅2 LiCl und 50 Mol‐% HCO2Na ermöglicht Kreuzkupplungen verschiedener N‐heterozyklischer Chloride und Bromide sowie aromatischer, halogenierter Ketone mit verschiedenen elektronenreichen und ‐armen Arylzinkreagentien. Die Reaktionen zeigen bei 25 °C innerhalb weniger Stunden eine vollständige Umsetzung.
Stable Alkynyl Glycosyl Carbonates: Catalytic Anomeric Activation and Synthesis of a Tridecasaccharide Reminiscent of Mycobacterium tuberculosis Cell Wall Lipoarabinomannan
Authors: Mishra Bijoyananda , Neralkar Mahesh , Hotha Srinivas
Published: February 2016

Oligosaccharide synthesis is still a challenging task despite the advent of modern glycosidation techniques. Herein, alkynyl glycosyl carbonates are shown to be stable glycosyl donors that can be activated catalytically by gold and silver salts at 25 °C in just 15 min to produce glycosides in excellent yields. Benzoyl glycosyl carbonate donors are solid compounds with a long shelf life. This operationally simple protocol was found to be highly efficient for the synthesis of nucleosides, amino acids, and phenolic and azido glycoconjugates. Repeated use of the carbonate glycosidation method enabled the highly convergent synthesis of tridecaarabinomannan in a rapid manner.
Size Fractionation of Two‐Dimensional Sub‐Nanometer Thin Manganese Dioxide Crystals towards Superior Urea Electrocatalytic Conversion
Authors: Chen Sheng , Duan Jingjing , Vasileff Anthony , Qiao Shi Zhang
Published: February 2016

A universal technique has been proposed to sort two‐dimensional (2D) sub‐nanometer thin crystals (manganese dioxide MnO2 and molybdenum disulfide MoS2) according to their lateral dimensions. This technique is based on tuning the zeta potential of their aqueous dispersions which induces the selective sedimentation of large‐sized 2D crystals and leaves the small‐sized counterparts in suspension. The electrocatalytic properties of as‐obtained 2D ultrathin crystals are strongly dependent on their lateral size. As a proof‐of‐concept study, the small‐sized MnO2 nanocrystals were tested as the electrocatalysts for the urea‐oxidation reaction (UOR), which showed outstanding performance in both half reaction and full electrolytic cell. A mechanism study reveals the enhanced performance is associated with the remarkable structural properties of MnO2 including ultrathin (ca. 0.95 nm), laterally small‐sized (50–200 nm), and highly exposed active centers.
Cyclic Hypervalent Iodine Reagents for Atom‐Transfer Reactions: Beyond Trifluoromethylation
Authors: Li Yifan , Hari Durga Prasad , Vita Maria Victoria , Waser Jerome
Published: February 2016

Hypervalent iodine compounds are privileged reagents in organic synthesis because of their exceptional reactivity. Among these compounds, cyclic derivatives stand apart because of their enhanced stability. They have been widely used as oxidants, but their potential for functional‐group transfer has only begun to be investigated recently. The use of benziodoxol(on)es for trifluoromethylation (Togni's reagents) is already widely recognized, but other transformations have also attracted strong interest recently. In this Review, the development in the area since 2011 will be presented. After a short summary of synthetic methods to prepare benziodoxol(on)e reagents, their use to construct carbon–heteroatom and carbon–carbon bonds will be presented. In particular, the introduction of alkynes by using ethynylbenziodoxol(on)e (EBX) reagents has been highly successful. Breakthroughs in the introduction of alkoxy, azido, difluoromethyl, and cyano groups will also be described.
Efficient MoS2 Exfoliation by Cross‐β‐Amyloid Nanotubes for Multistimuli‐Responsive and Biodegradable Aqueous Dispersions
Authors: Kapil Nidhi , Singh Ashmeet , Singh Manish , Das Dibyendu
Published: February 2016

Herein, we report the efficient exfoliation of MoS2 in aqueous medium by short cationic peptide nanotubes featuring the nucleating core 17LVFFA21 of β‐amyloid (Aβ 1–42), a sequence associated with Alzheimer's disease. The role of morphology, length, and nature of the amyloid surface on exfoliation/dispersions of MoS2 were investigated through specific mutations of the amyloid sequences. Notably, owing to the properties of both the constituents, self‐assembled soft nanostructures and MoS2, the hybrid dispersions responded reversibly to various stimuli, including temperature, pH, and light. Addition of a protease resulted in loss of the dispersions, which are otherwise stable for months at ambient conditions. The design flexibility of the peptide sequences, along with the stimuli‐responsiveness and biodegradability, can complement the applications of MoS2 in diverse fields.
C3′‐Deoxygenation of Paromamine Catalyzed by a Radical S‐Adenosylmethionine Enzyme: Characterization of the Enzyme AprD4 and Its Reductase Partner AprD3
Authors: Kim Hak Joong , LeVieux Jake , Yeh Yu‐Cheng , Liu Hung‐wen
Published: February 2016

C3′‐deoxygenation of aminoglycosides results in their decreased susceptibility to phosphorylation thereby increasing their efficacy as antibiotics. However, the biosynthetic mechanism of C3′‐deoxygenation is unknown. To address this issue, aprD4 and aprD3 genes from the apramycin gene cluster in Streptomyces tenebrarius were expressed in E. coli and the resulting gene products were characterized in vitro. AprD4 is shown to be a radical S‐adenosylmethionine (SAM) enzyme, catalyzing homolysis of SAM to 5′‐deoxyadenosine (5′‐dAdo) in the presence of paromamine. [4′‐2H]‐Paromamine was prepared and used to show that its C4′‐H is transferred to 5′‐dAdo by AprD4, during which the substrate is dehydrated to a product consistent with 4′‐oxolividamine. In contrast, paromamine is reduced to a deoxy product when incubated with AprD4/AprD3/NADPH. These results show that AprD4 is the first radical SAM diol‐dehydratase and, along with AprD3, is responsible for 3′‐deoxygenation in aminoglycoside biosynthesis.
Re‐engineering the Immune Response to Metastatic Cancer: Antibody‐Recruiting Small Molecules Targeting the Urokinase Receptor
Authors: Rullo Anthony F. , Fitzgerald Kelly J. , Muthusamy Viswanathan , Liu Min , Yuan Cai , Huang Mingdong , Kim Minsup , Cho Art E. , Spiegel David A.
Published: February 2016

Developing selective strategies to treat metastatic cancers remains a significant challenge. Herein, we report the first antibody‐recruiting small molecule (ARM) that is capable of recognizing the urokinase‐type plasminogen activator receptor (uPAR), a uniquely overexpressed cancer cell‐surface marker, and facilitating the immune‐mediated destruction of cancer cells. A co‐crystal structure of the ARM‐U2/uPAR complex was obtained, representing the first crystal structure of uPAR complexed with a non‐peptide ligand. Finally, we demonstrated that ARM‐U2 substantially suppresses tumor growth in vivo with no evidence of weight loss, unlike the standard‐of‐care agent doxorubicin. This work underscores the promise of antibody‐recruiting molecules as immunotherapeutics for treating cancer.
Boron(III)‐Containing Donor–Acceptor Compound with Goldlike Reflective Behavior for Organic Resistive Memory Devices
Authors: Poon Chun‐Ting , Wu Di , Yam Vivian Wing‐Wah
Published: February 2016

A small‐molecule‐based boron(III)‐containing donor–acceptor compound has been designed and synthesized. Interesting goldlike reflective behavior was observed in the neat thin‐film sample from simple spin‐coating preparation, which can serve as a potential organic thin‐film optical reflector. The small thickness in nanometer range and the relatively smooth surface morphology, together with simple preparation and easy solution processability, are attractive features for opening up new avenues for the fabrication of reflective coatings. Moreover, this donor–acceptor compound has been employed in the fabrication of organic resistive memory device, which exhibited good performance with low turn‐on voltage, small operating bias, large ON/OFF ratio, and long retention time.