bluuebunny/crossref_metadata_2025_split huggingface dataset:
JMJD6 is a driver of cellular proliferation and motility and a marker of poor prognosis in breast cancer
Authors: Lee Yi Fang , Miller Lance David , Chan Xiu Bin , Black Michael A , Pang Brendan , Ong Chee Wee , Salto-Tellez Manuel , Liu Edison T , Desai Kartiki V 
Published: May 2012

Abstract
Introduction
We developed an analytic strategy that correlates gene expression and clinical outcomes as a means to identify novel candidate oncogenes operative in breast cancer. This analysis, followed by functional characterization, resulted in the identification of Jumonji Domain Containing 6 (JMJD6) protein as a novel driver of oncogenic properties in breast cancer.

Methods
Through microarray informatics, Cox proportional hazards regression was used to analyze the correlation between gene expression and distant metastasis-free survival (DMFS) of patients in 14 independent breast cancer cohorts. JMJD6 emerged as a top candidate gene robustly associated with poor patient survival. Immunohistochemistry, siRNA-mediated silencing, and forced overexpression of JMJD6 in cell-based assays elucidated molecular mechanisms of JMJD6 action in breast cancer progression and shed light on the clinical breast cancer subtypes relevant to JMJD6 action.

Results
JMJD6 was expressed at highest levels in tumors associated with worse outcomes, including ER- and basal-like, Claudin-low, Her2-enriched, and ER+ Luminal B tumors. High nuclear JMJD6 protein was associated with ER negativity, advanced grade, and poor differentiation in tissue microarrays. Separation of ER+/LN- patients that received endocrine monotherapy indicated that JMJD6 is predictive of poor outcome in treatment-specific subgroups. In breast cancer cell lines, loss of JMJD6 consistently resulted in suppressed proliferation but not apoptosis, whereas forced stable overexpression increased growth. In addition, knockdown of JMJD6 in invasive cell lines, such as MDA-MB231, decreased motility and invasion, whereas overexpression in MCF-7 cells slightly promoted motility but did not confer invasive growth. Microarray analysis showed that the most significant transcriptional changes occurred in cell-proliferation genes and genes of the TGF-β tumor-suppressor pathway. High proliferation was characterized by constitutively high cyclin E protein levels. The inverse relation of JMJD6 expression with TGF-β
2
could be extrapolated to the breast cancer cohorts, suggesting that JMJD6 may affect similar pathways in primary breast cancer.

Conclusions
JMJD6 is a novel biomarker of tumor aggressiveness with functional implications in breast cancer growth and migration.
Consensus: a framework for evaluation of uncertain gene variants in laboratory test reporting
Authors: Crockett David K , Ridge Perry G , Wilson Andrew R , Lyon Elaine , Williams Marc S , Narus Scott P , Facelli Julio C , Mitchell Joyce A 
Published: May 2012

AbstractAccurate interpretation of gene testing is a key component in customizing patient therapy. Where confirming evidence for a gene variant is lacking, computational prediction may be employed. A standardized framework, however, does not yet exist for quantitative evaluation of disease association for uncertain or novel gene variants in an objective manner. Here, complementary predictors for missense gene variants were incorporated into a weighted Consensus framework that includes calculated reference intervals from known disease outcomes. Data visualization for clinical reporting is also discussed.
Teaching Note—Active Learning Exercise: Newspaper Page Layout
Authors: Devia Nelson , Weber Richard 
Published: May 2012

This exercise introduces students to the topics of modeling and mixed-integer programming and motivates them to investigate and understand the complexity of day-to-day problems. The activity consists of putting together a sheet of a newspaper using news and advertising items taken from a real newspaper. The objective is to arrive at a layout that has the highest possible value subject to the constraints of space on the sheet and the correct orientation of the items. Thus, the exercise poses a problem of optimization. The activity has all the necessary elements for use as an introduction to optimization and mixed-integer programming concepts, and it presents the students with a real-world situation that can also be seen as a game or competition. The enthusiasm this creates and the implicit difficulty of the actual problem motivate students to formalize the ideas involved and initiate a study of the basics of optimization techniques.
Amino acid properties may be useful in predicting clinical outcome in patients with Kir6.2 neonatal diabetes
Authors: Fraser Clementine S , Rubio-Cabezas Oscar , Littlechild Jennifer A , Ellard Sian , Hattersley Andrew T , Flanagan Sarah E 
Published: May 2012

BackgroundMutations in the KCNJ11 gene, which encodes the Kir6.2 subunit of the β-cell KATP channel, are a common cause of neonatal diabetes. The diabetes may be permanent neonatal diabetes mellitus (PNDM) or transient neonatal diabetes mellitus (TNDM), and in ∼20% of patients, neurological features are observed. A correlation between the position of the mutation in the protein and the clinical phenotype has previously been described; however, recently, this association has become less distinct with different mutations at the same residues now reported in patients with different diabetic and/or neurological phenotypes.MethodsWe identified from the literature, and our unpublished series, KCNJ11 mutations that affected residues harbouring various amino acid substitutions (AAS) causing differences in diabetic or neurological status. Using the Grantham amino acid scoring system, we investigated whether the difference in properties between the wild-type and the different AAS at the same residue could predict phenotypic severity.ResultsPair-wise analysis demonstrated higher Grantham scores for mutations causing PNDM or diabetes with neurological features when compared with mutations affecting the same residue that causes TNDM (P=0.013) or diabetes without neurological features (P=0.016) respectively. In just five of the 25 pair-wise analyses, a lower Grantham score was observed for the more severe phenotype. In each case, the wild-type residue was glycine, the simplest amino acid.ConclusionThis study demonstrates the importance of the specific AAS in determining phenotype and highlights the potential utility of the Grantham score for predicting phenotypic severity for novel KCNJ11 mutations affecting previously mutated residues.
Robust Estimation of Local Genetic Ancestry in Admixed Populations Using a Nonparametric Bayesian Approach
Authors: Sohn Kyung-Ah , Ghahramani Zoubin , Xing Eric P 
Published: May 2012

AbstractWe present a new haplotype-based approach for inferring local genetic ancestry of individuals in an admixed population. Most existing approaches for local ancestry estimation ignore the latent genetic relatedness between ancestral populations and treat them as independent. In this article, we exploit such information by building an inheritance model that describes both the ancestral populations and the admixed population jointly in a unified framework. Based on an assumption that the common hypothetical founder haplotypes give rise to both the ancestral and the admixed population haplotypes, we employ an infinite hidden Markov model to characterize each ancestral population and further extend it to generate the admixed population. Through an effective utilization of the population structural information under a principled nonparametric Bayesian framework, the resulting model is significantly less sensitive to the choice and the amount of training data for ancestral populations than state-of-the-art algorithms. We also improve the robustness under deviation from common modeling assumptions by incorporating population-specific scale parameters that allow variable recombination rates in different populations. Our method is applicable to an admixed population from an arbitrary number of ancestral populations and also performs competitively in terms of spurious ancestry proportions under a general multiway admixture assumption. We validate the proposed method by simulation under various admixing scenarios and present empirical analysis results from a worldwide-distributed dataset from the Human Genome Diversity Project.
Transvection Is Common Throughout the Drosophila Genome
Authors: Mellert David J , Truman James W 
Published: May 2012

Abstract
Higher-order genome organization plays an important role in transcriptional regulation. In Drosophila, somatic pairing of homologous chromosomes can lead to transvection, by which the regulatory region of a gene can influence transcription in trans. We observe transvection between transgenes inserted at commonly used phiC31 integration sites in the Drosophila genome. When two transgenes that carry endogenous regulatory elements driving the expression of either LexA or GAL4 are inserted at the same integration site and paired, the enhancer of one transgene can drive or repress expression of the paired transgene. These transvection effects depend on compatibility between regulatory elements and are often restricted to a subset of cell types within a given expression pattern. We further show that activated UAS transgenes can also drive transcription in trans. We discuss the implication of these findings for (1) understanding the molecular mechanisms that underlie transvection and (2) the design of experiments that utilize site-specific integration.
Divergent Functions Through Alternative Splicing: The Drosophila
CRMP Gene in Pyrimidine Metabolism, Brain, and Behavior
Authors: Morris Deanna H , Dubnau Josh , Park Jae H , Rawls John M 
Published: May 2012

Abstract
DHP and CRMP proteins comprise a family of structurally similar proteins that perform divergent functions, DHP in pyrimidine catabolism in most organisms and CRMP in neuronal dynamics in animals. In vertebrates, one DHP and five CRMP proteins are products of six genes; however, Drosophila melanogaster has a single CRMP gene that encodes one DHP and one CRMP protein through tissue-specific, alternative splicing of a pair of paralogous exons. The proteins derived from the fly gene are identical over 90% of their lengths, suggesting that unique, novel functions of these proteins derive from the segment corresponding to the paralogous exons. Functional homologies of the Drosophila and mammalian CRMP proteins are revealed by several types of evidence. Loss-of-function CRMP mutation modifies both Ras and Rac misexpression phenotypes during fly eye development in a manner that is consistent with the roles of CRMP in Ras and Rac signaling pathways in mammalian neurons. In both mice and flies, CRMP mutation impairs learning and memory. CRMP mutant flies are defective in circadian activity rhythm. Thus, DHP and CRMP proteins are derived by different processes in flies (tissue-specific, alternative splicing of paralogous exons of a single gene) and vertebrates (tissue-specific expression of different genes), indicating that diverse genetic mechanisms have mediated the evolution of this protein family in animals.
SNP-Ratio Mapping (SRM): Identifying Lethal Alleles and Mutations in Complex Genetic Backgrounds by Next-Generation Sequencing
Authors: Lindner Heike , Raissig Michael T , Sailer Christian , Shimosato-Asano Hiroko , Bruggmann Rémy , Grossniklaus Ueli 
Published: May 2012

AbstractWe present a generally applicable method allowing rapid identification of causal alleles in mutagenized genomes by next-generation sequencing. Currently used approaches rely on recovering homozygotes or extensive backcrossing. In contrast, SNP-ratio mapping allows rapid cloning of lethal and/or poorly transmitted mutations and second-site modifiers, which are often in complex genetic/transgenic backgrounds.
Mice deficient in p52/NF-κB as a model for studying prion disease
Authors: Poljak Ljiljana 
Published: May 2012

AbstractA tight functional link between the central nervous and peripheral immune system closely related to the activity of NF-κB transcription factor has been evidenced in numerous brain pathological conditions. One of the most instructive examples is a prion neuroinvasion and the development of transmissible spongioform encephalopathy (TSE) or prion diseases. The failure of peripherally administrated prions to elicit disease in immune-deficient mice indicates that preserved organ microarchitecture is crucial for TSE pathogenesis and it seems to go through topographic relationships between follicular dendritic cells and sympathetic endings in lymphoid organs. New insight into the molecular requirements for follicular dendritic cell (FDC) development in NF-κB p52 deficient mice highlights the role of NF-κB transcription factor in prion disease progression. However, adoptive transfer of wild type bone marrow cells (NF-κB +/+ background) into p52 deficient animals (NF-κB -/- background) does not correct the FDC defect. RT-PCR analysis of the expression level of mRNA for LTa, LTb, TNFRI and BLC of the splenic cells from p52/NF-κB mutant/wt BM chimera did not reveal major changes compared to wt/wt BM chimeras, indicating that their normal expression within splenic tissue does not assure for complete restoration of the FDC network in p52/NF-κB mutant. This implies that the distance between FDCs and splenic nerve terminals around the central arteriole is longer and could interfere with prion spreading in lymphoid organs prior to neuroinvasion. In light of the fact that prion neuroinvasion highly depends on the physical distance between sympathetic nerve endings and FDCs dendritic extensions, it is not hard to imagine that this could be the way to approach the problem of prion diseases development.
Malignant transformation of grade II ganglioglioma to glioblastoma: A case report
Authors: Čupić Hrvoje , Sajko Tomislav , Sesar Nikolina , Ivica Mihovil , Pažanin Leo 
Published: May 2012

AbstractGangliogliomas are well differentiated and slowly growing neuroepithelial tumors composed of neoplastic ganglion cells and neoplastic glial cells corresponding mostly to the World Health Organization grade I tumors. However, some of these tumors disclose histologically more malignant glial component and correspond to grade II or grade III tumors. We report a case of left temporal lobe tumor in a 42-year-old woman fulfilling the diagnostic criteria for atypical (grade II) ganglioglioma with high Ki-67 proliferation index and p53 immunoreactive tumor cells. In spite of gross total removal of the tumor, it recurred eight months after surgery. Histopathological examination of the recurrent tumor revealed that it had undergone malignant transformation into a glioblastoma. This case indicates that gangliogliomas with high Ki-67 proliferating index and p53 immunoreactivity should be carefully monitored for recurrence and malignant progression regardless of their morphological grading and seemingly total surgical removal.
PTEN: A molecular target for neurodegenerative disorders
Authors: Ismail Azza , Ning Ke , Al-Hayani Abdulmonem , Sharrack Basil , Azzouz Mimoun 
Published: May 2012

AbstractPTEN (phosphatase and tensin homologue deleted in chromosome 10) was first identified as a candidate tumour suppressor gene located on chromosome 10q23. It is considered as one of the most frequently mutated genes in human malignancies. Emerging evidence shows that the biological function of PTEN extends beyond its tumour suppressor activity. In the central nervous system PTEN is a crucial regulator of neuronal development, neuronal survival, axonal regeneration and synaptic plasticity. Furthermore, PTEN has been linked to the pathogenesis of neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. Recently increased attention has been focused on PTEN as a potential target for the treatment of brain injury and neurodegeneration. In this review we discuss the essential functions of PTEN in the central nervous system and its involvement in neurodegeneration.
Genetic animal models of Tourette syndrome: The long and winding road from lab to clinic
Authors: Cauchi Ruben , Tárnok Zsanett 
Published: May 2012

AbstractTourette syndrome (TS) is a disabling neuropsychiatric disorder characterised by persistent motor and vocal tics. TS is a highly comorbid state, hence, patients might experience anxiety, obsessions, compulsions, sleep abnormalities, depression, emotional liability, learning problems, and attention deficits in addition to tics. In spite of its complex heterogeneous genetic aetiology, recent studies highlighted a strong link between TS and genetic lesions in the HDC (L-histidine decarboxylase) gene, which encodes the enzyme that synthetises histamine, and the SLITRK1 (SLIT and TRK-like family member 1) gene, which encodes a transmembrane protein that was found to regulate neurite outgrowth. In addition to validating the contribution of a specific genetic aberration to the development of a particular pathology, animal models are crucial to dissect the function of disease-linked proteins, expose disease pathways through examination of genetic modifiers and discover as well as assess therapeutic strategies. Mice with a knockout of either Hdc or Slitrk1 exhibit anxiety and those lacking Hdc, display dopamine agonist-triggered stereotypic movements. However, the mouse knockouts do not spontaneously display tics, which are recognised as the hallmark of TS. In this review, we explore the features of the present genetic animal models of TS and identify reasons for their poor resemblance to the human condition. Importantly, we highlight ways forward aimed at developing a valuable genetic model of TS or a model that has good predictive validity in developing therapeutic drugs for the treatment of tics, hence potentially accelerating the arduous journey from lab to clinic.
Attentional biases to threat and serotonin transporter gene promoter (5-HTLPR) polymorphisms: Evidence from a probe discrimination task with endogenous cues
Authors: Miu Andrei , Vulturar Romana , Chiş Adina , Ungureanu Loredana 
Published: May 2012

AbstractRecent studies have investigated the association between serotonin transporter gene promoter (5-HTTLPR) functional polymorphisms and attentional biases to threat, a cognitive mechanism that probably contributes to the development and maintenance of anxiety. The present study genotyped a sample of N = 141 healthy volunteers for an insertion/deletion polymorphism and the rs25531 single-nucleotide polymorphism in 5-HTTLPR. In order to investigate attentional biases to threat, we used a probe discrimination task in which the gaze direction of centrally presented fearful or neutral faces endogenously cued attention. The results indicated no significant differences in attentional biases to threat between 5-HTTLPR genotype groups. However, we found that carriers of two low-expressing alleles (i.e., S or LG) of 5-HTTLPR displayed a significant slowing of responses across trials with fearful compared to neutral faces. This effect may indicate that fearful faces triggered increased emotional arousal in these genotypes, which may have interfered with the processing of gaze direction and spatial cuing. These results suggest that using fearful faces as endogenous spatial cues may be problematic in genotypes associated with facilitated emotional arousal to these stimuli, and underscore the hypothesis that 5-HTTLPR specifically influences automatic rather than consciously-controlled processes of attention.
Models of CNS injury in the nonhuman primate: A new era for treatment strategies
Authors: Teo Leon , Rosenfeld Jeffrey , Bourne James 
Published: May 2012

AbstractCentral nervous system (CNS) injuries affect all levels of society indiscriminately, resulting in functional and behavioral deficits with devastating impacts on life expectancies, physical and emotional wellbeing. Considerable literature exists describing the pathophysiology of CNS injuries as well as the cellular and molecular factors that inhibit regrowth and regeneration of damaged connections. Based on these data, numerous therapeutic strategies targeting the various factors of repair inhibition have been proposed and on-going assessment has demonstrated some promising results in the laboratory environ. However, several of these treatment strategies have subsequently been taken into clinical trials but demonstrated little to no improvement in patient outcomes. As a result, options for clinical interventions following CNS injuries remain limited and effective restorative treatment strategies do not as yet exist. This review discusses some of the current animal models, with focus on nonhuman primates, which are currently being modeled in the laboratory for the study of CNS injuries. Last, we review the current understanding of the mechanisms underlying repair/regrowth inhibition and the current trends in experimental treatment strategies that are being assessed for potential translation to clinical applications.
The meaning of ṭuppi
Authors: Baker Heather D. 
Published: May 2012

Résumé Le sens du mot akkadien ṭuppi a fait l’objet de vifs débats entre assyriologues depuis près d’un siècle. Le présent article propose que ṭuppi , qu’on trouve communément dans des expressions temporelles, ne peut que désigner une période d’un an. Cette proposition résulte de l’observation que, dans le corpus non négligeable des contrats néo-babyloniens de location de maison, aucun texte ne se réfère explicitement à une période de location d’un an. Étant donné que des périodes de durée relativement courte sont par ailleurs assez communes, cette lacune étonnante dans les données est difficile à expliquer, sauf si l’expression adi ṭuppišu (et ses variantes) est comprise comme « pour une période d’un an ». La même conclusion s’applique à d’autres catégories de documents qui impliquent une échéance, comme les contrats d’apprentissage. L’article discute les implications de cette découverte pour l’interprétation d’une large série de documents juridiques et administratifs et de lettres, certains apportant des éléments de confirmation. Il examine également les textes historiques où ṭuppi apparaît, à savoir la liste royale assyrienne et l’inscription du 8ème siècle de Ninurta-kudurrī-uṣur, gouverneur de Mari et du Sūḫu. On considère que - šu dans ṭuppišu est redondant, ce qui affecte l’interprétation de ces textes puisque - šu a parfois été compris comme se référant à à un prédécesseur antérieur au roi concerné. La conséquence pour la chronologie de la mésopotamie de l’interprétation de ṭuppišu ici proposée n’est cependant pas considérable, car le consens avait tendu à affecter une durée entre 0 et 2 ans aux règnes ṭuppišu de la liste royale assyrienne. Cependant, cette interprétation de ṭuppišu comme une période d’un an clarifie certains passages de ces textes historiques restés énigmatique.