bluuebunny/crossref_metadata_2025_split huggingface dataset:
Computational Prediction of Genetic Drivers in Cancer
Authors: Djotsa Nono Alice B , Chen Ken , Liu Xiaoming 
Published: February 2016

AbstractCancer 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 ConceptsCancer 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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract

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.
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

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

ObjectiveTo 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.MethodsAn 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.ResultsThe 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.ConclusionWe 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

ObjectiveTo 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.MethodsAnkylosing 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.ResultsA 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.ConclusionPhysical 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

SummaryThe 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.
Palladium‐Catalyzed Carbonylative Multicomponent Synthesis of Functionalized Benzimidazothiazoles
Authors: Veltri Lucia , Grasso Giuseppe , Rizzi Rosanna , Mancuso Raffaella , Gabriele Bartolo 
Published: February 2016

AbstractThe 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

AbstractAn 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

BackgroundInvestigations 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.MethodsEndoscopic 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.ResultsIn 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.ConclusionThis 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.