bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical and Phenotypic Relevance of
cis
‐Acting Regulatory Polymorphisms
Authors: Liebert Anke , Jones Bryony L , Swallow Dallas M 
Published: May 2014

Abstract

Genetic variants that regulate the expression level of a transcript are known as expression quantitative trait loci (eQTLs) or regulatory single nucleotide polymorphisms.
Cis
‐variants are those that only act on a target gene (or genes) on the same chromosomal homologue. They cause additive differences in gene expression that are tightly associated with the three genotypes of the regulatory eQTL, and cause allelic expression imbalance in heterozygous samples. Unlike
trans
‐variants, which can act on many genes located at a distance,
cis
‐acting variants are less likely to have all‐or‐none effects if inactivated, and these may be tissue specific and thus less severe. Such
cis
‐variants are found occasionally in Mendelian disease and now increasingly implicated in polygenic disorders. The interactions of these regulatory variations with other genetic and also environmental factors are likely to account for some of the complexity of multifactorial diseases.

Key Concepts:

Regulatory polymorphisms, otherwise known as eQTLs (expression quantitative trait loci), are DNA sequence variations that alter the level of expression of particular transcripts.

Cis
‐eQTLs are
cis
‐acting polymorphisms that cause variation in the expression of a nearby gene or genes on the same chromosomal homologue.

In heterozygous individuals there is a difference in the level of expression from each of the pair of genes transcribed from the two chromosomal homologues.

This difference in expression in heterozygous individuals can be observed as allelic expression imbalance (AEI) if there are also allelic sequence differences in the transcript.

Such AEI is distinguishable from imprinting in that unlike the case of imprinting the higher expressing transcript can come from either the mother or the father.

Cis
‐acting polymorphisms can affect expression in a tissue‐specific and developmentally specific manner.

They are strong candidates for positive selection and evolutionary adaptation but such variants might be maladaptive in different environments.

Cis
‐acting regulatory sequence changes have been identified as a class of rare mutations in Mendelian disorders, and more common variants are increasingly implicated as causal polymorphisms involved in multifactorial diseases.
Genetic Susceptibility to Triple‐Negative Breast Cancers
Authors: Wong‐Brown Michelle W , Scott Rodney J 
Published: May 2014

Abstract

Triple‐negative breast cancer (TNBC) is a histological classification of breast cancer, where there is no expression of either the oestrogen or the progesterone receptor and no amplification of the HER2 receptor. TNBC is an important breast cancer subtype as it is aggressive in nature and has a poorer disease prognosis, mainly due to a paucity of targeted therapies. Studies in recent years have tried to elucidate the genetic aetiology of TNBC to better understand the disease and to predict response to treatments based on their genetic profile. TNBC has been shown to be very similar to
BRCA1
mutation‐associated breast tumours, where it is estimated that approximately 20% of TNBC patients harbour germline
BRCA
(especially
BRCA1
) mutations. The contribution of germline mutations in other breast cancer susceptibility genes to TNBC still remains to be determined. Several common and novel breast cancer susceptibility loci have also been specifically linked to TNBC. These findings support the argument that genetic testing should be offered to patients based on the triple‐negative phenotype of their breast tumours.

Key Concepts:

TNBC is an important area of study due to the aggressive nature of this tumour subtype and the difficulties in disease treatment.

Women with TNBC have a poorer prognosis due to lack of endocrine therapies.

TNBC has histopathological characteristics similar to
BRCA1
‐ and
BRCA
2‐associated tumours, and could have similar molecular aetiology.

Germline mutations in
BRCA1
and
BRCA2
have been associated with up to 20% of TNBC cohorts unselected for family history of the disease.

The contribution of germline mutations in other breast cancer susceptibility genes to TNBC remains to be determined.

Several known breast cancer susceptibility loci have been shown to be specifically associated with TNBC.

Patients with TNBC could benefit from genetic screening of both
BRCA
genes based solely on the phenotype of their breast tumour.
Role of Chromosomal Reorganisations in the Human–Chimpanzee Speciation
Authors: Farré Marta , Ruiz‐Herrera Aurora 
Published: May 2014

Abstract

The elucidation of how recombination is shaping the genomic architecture of organisms and, more in particular, how this affects the speciation process has been a long‐standing question in evolutionary biology. Large‐scale genomic changes such as inversions, translocations, fusions and fissions contribute to the reshuffling of genomes, providing new chromosomal forms on which natural selection can work. Despite large efforts employed in the last decade, few empirical data are available on the mechanisms by which genome reshuffling contribute to the formation of new species. Here, the authors discuss on the models of chromosomal evolution and the contribution of chromosomal reorganisations in mammalian chromosome evolution, and more specifically, during the human–chimpanzee speciation event.

Key Concepts:

The evolutionary process by which new biological species arise (speciation) is a complex process that requires the understanding of many mechanisms such as reproductive isolation, patterns of species diversity, together with the genetic basis underlying the process.

Understanding the mechanisms by which reproductive isolation (breakdown of gene flow between two populations) is achieved, is fundamental for speciation.

Genetic speciation makes references to the group of genes that are involved in maintaining reproductive isolation between species.

Chromosomal reorganisations may contribute to speciation due to the underdominant fitness effects associated with meiotic abnormalities when occurring in heterozygotes.

Chromosome rearrangements, such as inversions, can suppress recombination thus contributing to a reduction of gene flow across genomic regions and the accumulation of genetic incompatibilities.
Slice Culture Method for Studying Migration of Neuronal Progenitor Cells Derived from Human Embryonic Stem Cells (hESC)
Authors: Filipovic Radmila , Kumar Saranya Santosh , Bahr Ben A. , Loturco Joseph 
Published: May 2014

AbstractIn this unit we describe an overlay brain slice culture assay for studying migration of transgenic neurospheres derived from human embryonic stem cells (hESC). Neuronal progenitor cells were generated from hESC by derivation of embryoid bodies and rosettes. Rosettes were transfected using the PiggyBac transposon system with either control plasmids (GFP) or plasmid encoding a gene important for migration of neuronal progenitor cells, Doublecortin (DCX). Transfected cells were subsequently grown in low‐adhesion plates to generate transgenic human neurospheres (t‐hNS). Organotypic slice cultures were prepared from postnatal rat forebrain and maintained using the interface method, before transfected t‐hNS were overlaid below the cortex of each hemisphere. After 1 to 5 days, forebrain slices were fixed and processed for immunofluorescence. The distance at which cells migrated from the center of neurospheres to the host forebrain tissue was measured using Image J software. This protocol provides details for using the slice culture method for studying migration and integration of human neuronal cells into the host brain tissue. Curr. Protoc. Stem Cell Biol. 29:1H.7.1‐1H.7.14. © 2014 by John Wiley & Sons, Inc.
Generation of GFP Reporter Human Induced Pluripotent Stem Cells Using AAVS1 Safe Harbor Transcription Activator‐Like Effector Nuclease
Authors: Luo Yongquan , Rao Mahendra , Zou Jizhong 
Published: May 2014

AbstractGeneration of a fluorescent GFP reporter line in human induced pluripotent stem cells (hiPSCs) provides enormous potentials in both basic stem cell research and regenerative medicine. A protocol for efficiently generating such an engineered reporter line by gene targeting is highly desired. Transcription activator‐like effector nucleases (TALENs) are a new class of artificial restriction enzymes that have been shown to significantly promote homologous recombination by >1000‐fold. The AAVS1 (adeno‐associated virus integration site 1) locus is a “safe harbor” and has an open chromatin structure that allows insertion and stable expression of transgene. Here, we describe a step‐by‐step protocol from determination of TALENs activity, hiPSC culture, and delivery of a donor into AAVS1 targeting site, to validation of targeted integration by PCR and Southern blot analysis using hiPSC line, and a pair of open‐source AAVS1 TALENs. Curr. Protoc. Stem Cell Biol. 29:5A.7.1‐5A.7.18. © 2014 by John Wiley & Sons, Inc.
Electrocardiographic Findings in Systemic Lupus Erythematosus: Data From an International Inception Cohort
Authors: Bourré‐Tessier Josiane , Urowitz Murray B. , Clarke Ann E. , Bernatsky Sasha , Krantz Mori J. , Huynh Thao , Joseph Lawrence , Belisle Patrick , Bae Sang‐Cheol , Hanly John G. , Wallace Daniel J. , Gordon Caroline , Isenberg David , Rahman Anisur , Gladman Dafna D. , Fortin Paul R. , Merrill Joan T. , Romero‐Diaz Juanita , Sanchez‐Guerrero Jorge , Fessler Barri , Alarcón Graciela S. , Steinsson Kristján , Bruce Ian N. , Ginzler Ellen , Dooley Mary Anne , Nived Ola , Sturfelt Gunnar , Kalunian Kenneth , Ramos‐Casals Manuel , Petri Michelle , Zoma Asad , Pineau Christian A. 
Published: May 2014

ObjectiveTo estimate the early prevalence of various electrocardiographic (EKG) abnormalities in patients with systemic lupus erythematosus (SLE) and to evaluate possible associations between repolarization changes (increased corrected QT [QTc] and QT dispersion [QTd]) and clinical and laboratory variables, including the anti‐Ro/SSA level and specificity (52 or 60 kd).MethodsWe studied adult SLE patients from 19 centers participating in the Systemic Lupus International Collaborating Clinics (SLICC) Inception Registry. Demographics, disease activity (Systemic Lupus Erythematosus Disease Activity Index 2000 [SLEDAI‐2K]), disease damage (SLICC/American College of Rheumatology Damage Index [SDI]), and laboratory data from the baseline or first followup visit were assessed. Multivariate logistic and linear regression models were used to asses for any cross‐sectional associations between anti‐Ro/SSA and EKG repolarization abnormalities.ResultsFor the 779 patients included, mean ± SD age was 35.2 ± 13.8 years, 88.4% were women, and mean ± SD disease duration was 10.5 ± 14.5 months. Mean ± SD SLEDAI‐2K score was 5.4 ± 5.6 and mean ± SD SDI score was 0.5 ± 1.0. EKG abnormalities were frequent and included nonspecific ST‐T changes (30.9%), possible left ventricular hypertrophy (5.4%), and supraventricular arrhythmias (1.3%). A QTc ≥440 msec was found in 15.3%, while a QTc ≥460 msec was found in 5.3%. Mean ± SD QTd was 34.2 ± 14.7 msec and QTd ≥40 msec was frequent (38.1%). Neither the specificity nor the level of anti‐Ro/SSA was associated with QTc duration or QTd, although confidence intervals were wide. Total SDI was significantly associated with a QTc interval exceeding 440 msec (odds ratio 1.38 [95% confidence interval 1.06, 1.79]).ConclusionA substantial proportion of patients with recent‐onset SLE exhibited repolarization abnormalities, although severe abnormalities were rare.
Patient and Physician Expectations of Add‐On Treatment With Golimumab for Rheumatoid Arthritis: Relationships Between Expectations and Clinical and Quality of Life Outcomes
Authors: Dasgupta Bhaskar , Combe Bernard , Louw Ingrid , Wollenhaupt Jürgen , Zerbini Cristiano A. F. , Beaulieu Andre , Schulze‐Koops Hendrik , Durez Patrick , Wolff Verónica , Yao Ruji , Weng Haoling H. , Govoni Marinella , Vastesaeger Nathan 
Published: May 2014

ObjectiveRheumatoid arthritis (RA) management involves improving clinical outcomes and quality of life (QOL). Golimumab is used as add‐on therapy for patients who have failed disease‐modifying antirheumatic drugs (DMARDs). This GO‐MORE subanalysis investigated relationships between patient and physician expectations and outcomes.MethodsGO‐MORE was an open‐label, multinational, prospective study in biologic agent–naive patients with active RA despite DMARD treatment. Patients received 50 mg subcutaneous golimumab monthly for 6 months. At baseline and month 3, patients rated treatment expectations for the following 3 months using 5‐point scales (where 1 = good and 5 = poor). Outcomes were compared among expectation tertiles: most positive, intermediate, and least positive. At baseline and month 3, physicians predicted patient disease state 3 months later.ResultsAt baseline, 3,280 efficacy‐evaluable patients with moderate (21.3%) or high (78.7%) disease activity had mean ± SD disease duration of 7.6 ± 7.9 years, mean ± SD Health Assessment Questionnaire (HAQ) disability index (DI) score of 1.44 ± 0.67, and mean ± SD EuroQol 5‐domain (EQ‐5D) score of 0.42 ± 0.33. Patients reported high treatment expectations (mean 1.43); 95.9% expected golimumab to be better than current treatment. Patients with fewer DMARD failures, higher disease activity, shorter disease duration, younger age, and female sex reported higher expectations (P < 0.05 for all). After 6 months, patients with the most positive expectations had higher remission rates (P < 0.0001) and greater HAQ DI (P < 0.0001) and EQ‐5D (P < 0.0001) score improvements. At baseline, physicians expected 29.6% and 59.2% of patients to attain remission and low disease activity, respectively, after 3 months.ConclusionPatients had high expectations for golimumab treatment. Patients with more positive expectations had greater remission rates, improvements in function, and QOL.
Relevant Concepts of Functioning for Patients With Systemic Lupus Erythematosus Identified in a Delphi Exercise of Experts and a Literature Review
Authors: Leuchten Nicolai , Bauernfeind Bettina , Kuttner Johannes , Stamm Tanja , Smolen Josef S. , Pisetsky David S. , Aringer Martin 
Published: May 2014

ObjectiveTo identify in a Delphi exercise of international systemic lupus erythematosus (SLE) experts and a systematic literature review the most relevant concepts that impact on the functioning of SLE patients.MethodsSixty SLE experts participated in all rounds of a 3‐round e‐mail–based Delphi exercise; for the literature review, 573 manuscripts out of 4 decades were analyzed. Concepts in the first Delphi round and from the literature were linked to categories of the International Classification of Functioning, Disability and Health (ICF). Categories were voted on individually in a feedback‐driven Delphi process, and ranked by frequency in the literature, respectively.ResultsIn the Delphi exercise, at least 80% of the participants found 30 categories of the domain body functions and structures, and 3 categories in the domain activities and participation and environmental factors important. In general, the categories identified in the literature review overlapped with those in the Delphi exercise with regard to body functions and structures, while showing some differences in other domains. The highest agreement concerned the ICF categories “joints,” “skin and related structures,” “fatiguability,” “immunological system functions,” and “handling stress and other psychological demands.” Agreement with an earlier patient Delphi exercise was considerable.ConclusionA 3‐step Delphi exercise of 60 SLE experts and a literature review identified a wide spectrum of relevant ICF categories with impact on functioning of SLE patients. The categories derived from these approaches overlap with each other and with those of a patient Delphi exercise.
Systemic Lupus Erythematosus and Outcomes in First and Subsequent Births Based on Data From a National Birth Registry
Authors: Wallenius Marianne , Salvesen Kjell Å. , Daltveit Anne K. , Skomsvoll Johan F. 
Published: May 2014

ObjectiveTo examine the associations between systemic lupus erythematosus (SLE) and outcomes in first and subsequent births.MethodsData from the Medical Birth Registry of Norway during the period December 1, 1998 to December 31, 2009 were used to assess maternal and perinatal outcomes in women diagnosed with SLE compared with the general population. Outcomes of first and subsequent births were analyzed separately. Associations between SLE and pregnancy outcomes were assessed in logistic regression analyses and are shown as adjusted odds ratios (aORs) after adjustment for maternal age, gestational age, smoking habits, and previous cesarean section (CS), when relevant.ResultsWe analyzed 95 first and 145 subsequent births in patients and compared them with references. The risk of CS was two‐fold higher in SLE patients in first and subsequent births. More newborns of patients had a birth weight <2,500 gm (aOR 5.00 [95 % confidence interval (95% CI) 3.02, 8.27] in first births and aOR 4.33 [95% CI 2.64, 7.10] in subsequent births). Additionally, preterm birth was more frequent among SLE patients (aOR 4.04 [95% CI 2.45, 6.56] in first births and aOR 3.13 [95% CI 1.97, 4.98] in subsequent births). Congenital malformations were more prevalent among children of patients than references (aOR 2.71 [95% CI 1.25, 5.86] in first births and aOR 3.13 [95% CI 1.69, 5.79] in subsequent births). Perinatal death was more frequent in first births among patients (aOR 7.34 [95% CI 2.69, 20.03]), but no difference was observed in subsequent births.ConclusionPregnancy complications were more frequent in SLE patients than references, and the greatest differences between groups were observed in first births.
Influence of a Nanometric Al2O3 Interlayer on the Thermal Conductance of an Al/(Si, Diamond) Interface
Authors: Monachon Christian , Weber Ludger 
Published: May 2014

AbstractThe effect of an Al2O3 interlayer on the thermal conductance of metal (Al)/non‐metal (diamond and silicon) interfaces is investigated using Time Domain ThermoReflectance (TDTR). Interlayers between 1.7 and 20 nm are deposited on oxygen‐terminated diamond and hydrogen‐terminated silicon substrates using atomic layer deposition (ALD). Their overall conductance is then measured at temperatures ranging from 78 to 290 K. The contributions of the interlayer bulk and its interfaces with both substrate and metallic overlayer are then separated. Values thus obtained for the bulk interlayer conductivity are comparable with existing data, reaching 1.25 W m−1 K−1 at 290 K. Interface contributions are shown to be very similar to the values obtained when a single Al/substrate interface is investigated, suggesting that interfacial oxides may govern TBC independently of the interlayer's thickness.
Maternal predictors of anxiety risk in young males with fragile X
Authors: Tonnsen Bridgette L. , Cornish Kim M. , Wheeler Anne C. , Roberts Jane E. 
Published: May 2014

AbstractChildren with fragile X syndrome (FXS) demonstrate high rates of anxiety disorders, with 65–83% meeting diagnostic criteria. The severity of anxiety symptoms in FXS has been shown to be partially predicted by elevated negative affect across early childhood [Tonnsen et al. (2013a); J Abnorm Child Psychol 41:267–280]. This association suggests that biologically driven vulnerability emerges early in development, as is reported in non‐clinical populations. However, anxiety emergence is likely moderated by multifaceted genetic, biological and environmental risk and protective factors. Mothers with the FMR1 premutation have been shown to exhibit elevated parenting stress and internalizing symptoms, which have each been associated with child behavior problems [Bailey et al. (2008a); Am J Med Genet Part A 146A:2060–2069 and Bailey et al. (2008b) Am J Med Genet Part A 146A:720–729]. Despite these findings, it is unclear whether maternal factors directly relate to anxiety vulnerability in high‐risk children with FXS, a question essential to informing targeted, family‐sensitive treatment. The present study examines how maternal protective and risk factors relate to child inhibition reflected in (1) child anxiety symptoms, (2) child trajectories of negative affect, and (3) the association between child anxiety and negative affect. Primary predictors include maternal parenting stress, indicators of mental health risk (anxiety and depressive symptoms), and maternal optimism. We also examine genetic correlates in mothers (CGG repeats, activation ratio, mRNA). Our findings suggest that behavioral inhibition in young children with FXS is associated with higher parenting stress and lower optimism, and higher parenting stress is associated with lower maternal X‐activation ratio. These findings underscore the need for family‐sensitive treatment strategies for anxiety disorders in children with FXS. © 2014 Wiley Periodicals, Inc.
Specific pattern of gadolinium enhancement in spondylotic myelopathy
Authors: Flanagan Eoin P. , Krecke Karl N. , Marsh Richard W. , Giannini Caterina , Keegan B. Mark , Weinshenker Brian G. 
Published: May 2014

ObjectiveTo highlight a specific under‐recognized radiological feature of spondylotic myelopathy often resulting in misdiagnosis.MethodsPatients evaluated between January 1, 1996 and December 31, 2012 who met the following criteria were included: (1) spondylotic myelopathy was suspected, (2) gadolinium enhancement was detected, and (3) spinal surgery was performed.ResultsFifty‐six patients (70% men) whose median age was 53.5 years (range = 24–80) were included. Spinal cord magnetic resonance imaging (cervical in 52; thoracic in 4) revealed longitudinal spindle‐shaped T2‐signal hyperintensity (100%) and cord enlargement (79%) accompanied by a characteristic pancakelike transverse band of gadolinium enhancement in 41 (73%), typically immediately caudal to the site of maximal spinal stenosis. Forty (71%) patients were initially diagnosed with neoplastic or inflammatory myelopathies, and decompressive surgery was delayed by a median of 11 months (range = 1–64). Spinal cord biopsy in 6 did not reveal any alternative diagnosis. Ninety‐five percent were stable or improved. Gadolinium enhancement persisted in 75% at 12 months, raising concern about the accuracy of the initial diagnosis. Twenty patients required a gait aid (36%) at last follow‐up (median = 60 months, range = 10–172). The need for a gait aid preoperatively (p = 0.005), but not delay of surgery, predicted the need for gait aid at final follow‐up.InterpretationTransverse pancakelike gadolinium enhancement associated with and just caudal to the site of maximal stenosis and at the rostrocaudal midpoint of a spindle‐shaped T2 hyperintensity suggests that spondylosis is the cause of the myelopathy. Persistent enhancement for months to years following decompressive surgery is common. Recognition is important to prevent inappropriate interventions or delay in consideration of a potentially beneficial decompressive surgery. Ann Neurol 2014;76:54–65