bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hsa_circ_0001947 suppresses acute myeloid leukemia progression by sponging hsa-miR-329-5p and regulating CREBRF expression
Authors: Han Fengjiao , Zhong Chaoqin , Li Wei , Wang Ruiqing , Zhang Chen , Yang Xinyu , Ji Chunyan , Ma Daoxin 
Published: September 2019

AbstractAcute myeloid leukemia (AML) is a heterogeneous group of diseases resulting from clonal transformation of hematopoietic precursors through the acquisition of chromosomal rearrangements and multiple gene mutations. Accumulating evidence has indicated that aberrantly expressed circular RNAs (circRNAs) are involved in cancer development and progression. However, their clinical values and biological roles in AML remain unclear. In this study, we identified the aberrantly down-regulated profile of hsa_circ_0001947 in AML through microarray analysis and validated it with quantitative reverse transcription polymerase chain reaction (qRT-PCR). Then, we explored the clinical significance, biological functions and regulatory mechanisms of hsa_circ_0001947 in AML patients. The results showed that lower hsa_circ_0001947 expression was positively correlated with higher leukemia cells in bone marrow or peripheral blood, indicating poor prognosis. Further, bioinformatics analysis demonstrated hsa_circ_0001947-hsa-miR-329-5p-CREBRF network. Down-regulation of hsa_circ_0001947 by siRNA promoted cell proliferation, inhibited apoptosis, reduced drug resistance of AML cells, and also decreased the expression of its targeted gene, CREBRF. The mimics of hsa-miR-329-5p reduced drug resistance and decreased the expression of CREBRF, while its inhibitor manifested anti-leukemia effects and increased CREBRF expression. In vivo studies revealed that silencing hsa_circ_0001947 promoted the tumor growth in BALB/c nude mice. Collectively, our findings suggest that hsa_circ_0001947 functions as a tumor inhibitor to suppress AML cell proliferation through hsa-miR-329-5p/CREBRF axis, which would be a novel target for AML therapy.
DETECTing Merkel cell Polyomavirus in Merkel Tumours
Authors: Arora Reety , Gupta Komal , Vijaykumar Anjali , Krishna Sudhir 
Published: September 2019

AbstractMerkel cell carcinoma (MCC) is a rare, aggressive skin cancer caused either by Merkel cell polyomavirus (MCV) T antigen expression, post integration (∼80% cases), or by UV mediated DNA damage. Interestingly, overall survival of patients suffering from MCV positive Merkel cell carcinoma is better, making this differential information of significant diagnostic and prognostic value. Also, MCV as a causative agent also provides a direct target for therapy in virus positive MCC patients. Currently, the methods used for diagnosis of MCV in tumours are often tedious, discordant and unreliable. In this study we used a guided molecular scissors based - DNA Endonuclease Targeted CRISPR Trans Reporter (DETECTR) technique to develop anin vitromolecular diagnostic tool for MCV positive MCC. DETECTR couples recombinase polymerase based amplification of target MCV DNA with Cas12a mediated detection. CRISPR diagnostics couple specific detection followed by cutting of the pathogenic DNA by the Cas enzyme – gRNA complex, with non-specific cutting of ssDNA that provides a measurable visual cue. To detect MCV DNA in MCC tumours, we designed Cas12a gRNAs targeting the MCV DNA and tested their targeting efficiency, and sensitivity using a fluorophore quencher labeled reporter assay. We show that this sophisticated MCV DETECTR system can detect MCV integrated in Merkel tumour rapidly, specifically and with femto-molar sensitivity. This new MCV DNA detecting system is promising and we hope it can be coupled with histopathological and immunohistochemical studies to diagnose the viral status of MCC in clinics in the near future.
Cell cycle regulation of mitochondrial protein import revealed by genome-scale pooled bimolecular fluorescence complementation screening
Authors: Blakely Kim , Mero Patricia , Arnold Roland , Saleem Ayesha , Misquitta Christine , Kasimer Dahlia , Kumar Sachin , Uetrecht Andrea , Brown Kevin A. , Datti Alessandro , Hood David , Kim Philip , Moffat Jason 
Published: September 2019

ABSTRACTA central focus of systems biology is the functional mapping of protein-protein interactions under physiological conditions. Here we describe MaGiCaL-BiFC, a lentivirus-based bimolecular fluorescence protein-fragment complementation approach for the high-throughput, genome-scale identification of protein-protein interactions in mammalian cells. After developing and validating this methodology using known protein-protein interaction pairs, we constructed genome-scale pooled BiFC libraries using the human ORFeome cDNA collection. These pooled libraries, containing ∼ 12,000 unique human cDNAs, were used to screen for candidate interaction partners of the mitochondrial transmembrane protein TOMM22. Following infection of cells with the TOMM22 bait and the pooled cDNA libraries, cells harboring candidate TOMM22 interacting proteins were isolated from the cell pool via fluorescence activated cell sorting, and identified via microarray analysis. This approach identified several known interaction partners of TOMM22, as well as novel physical and functional partners that link the mitochondrial network to proteins involved in diverse cellular processes. Notably, protein kinase CK2 was identified as a novel physical interaction partner of human TOMM22. We found that this association occurs preferentially during mitosis and involves direct phosphorylation of TOMM22, an event that may lead to attenuation of mitochondrial protein import. Together, this data contributes to the growing body of evidence suggesting eloquent coordination between cell cycle progression and mitochondrial physiology. Importantly, through high-throughput screening and focused validation, our study demonstrates the power of the MaGiCaL-BiFC approach to uncover novel functional protein-protein interactions, including those involving proteins with membrane-spanning domains, or of a transient nature, all within their native cellular environment.
The occasional perils of reflection (across the midline; in geometric morphometrics)
Authors: Katz David C. 
Published: September 2019

AbstractManually collecting landmark data on a large biological sample takes a long time. Several options exist to speed data collection, though each strategy introduces problems or raises concerns of its own. For bilaterally symmetric structures (e.g., crania), some recent papers recommend limiting landmark collection to one side and the midline, then “mirror-reflecting” landmarks across the midline to produce an approximation of the true bilateral configuration. However, where the midline is narrow relative to the bilateral anatomy, net midline landmark deviations from the mid-sagittal axis or plane will distort the mirror-reflected configuration. Here, I test whether this is a substantive concern at the scale of real biology. To do so, I simulate small amounts of mediolateral error on the mean shape from a sample of human mandibles (n= 178), then compare the distribution of simulated forms to variation in the data. I also test how faithfully mirror-reflected configurations replicate bilateral shape and size relationships. In both analyses, midline deviations from symmetry create striking distortions. I go on to show that incorporating a small number of landmarks from the opposite side of the mandible produces far more accurate estimates of bilateral shape than does mirror reflection. Mirror reflection is clearly inappropriate for these data and is likely suspect in all cases of narrow midline morphology.
The evolutionary plasticity of chromosome metabolism allows adaptation to DNA replication stress
Authors: Fumasoni Marco , Murray Andrew W. 
Published: September 2019

AbstractChromosome metabolism is defined by the pathways that collectively maintain the genome, including chromosome replication, repair and segregation. Because aspects of these pathways are conserved, chromosome metabolism is considered resistant to evolutionary change. We used the budding yeast,Saccharomyces cerevisiae, to investigate the evolutionary plasticity of chromosome metabolism. We experimentally evolved cells constitutively experiencing DNA replication stress caused by the absence of Ctf4, a protein that coordinates the activities at replication forks. Parallel populations adapted to replication stress, over 1000 generations, by acquiring multiple, successive mutations. Whole-genome sequencing and testing candidate mutations revealed adaptive changes in three aspects of chromosome metabolism: DNA replication, DNA damage checkpoint and sister chromatid cohesion. Although no gene was mutated in every population, the same pathways were sequentially altered, defining a functionally reproducible evolutionary trajectory. We propose that this evolutionary plasticity of chromosome metabolism has important implications for genome evolution in natural populations and cancer.
Effective CRISPRa-Mediated Control of Gene Expression in Bacteria Must Overcome Strict Target Site Requirements
Authors: Fontana Jason , Dong Chen , Kiattisewee Cholpisit , Chavali Venkata P. , Tickman Benjamin I. , Carothers James M. , Zalatan Jesse G. 
Published: September 2019

AbstractIn bacterial systems, CRISPR-Cas transcriptional activation (CRISPRa) has the potential to dramatically expand our ability to regulate gene expression, but we currently lack a complete understanding of the rules for designing effective guide RNA target sites. We have identified multiple features of bacterial promoters that impose stringent requirements on bacterial CRISPRa target sites. Most importantly, we found that shifting a gRNA target site by 2-4 bases along the DNA target can cause a nearly complete loss in activity. The loss in activity can be rescued by shifting the target site 10-11 bases, corresponding to one full helical turn. Practically, our results suggest that it will be challenging to find a gRNA target site with an appropriate PAM sequence at precisely the right position at arbitrary genes of interest. To overcome this limitation, we demonstrate that a dCas9 variant with expanded PAM specificity allows activation of promoters that cannot be activated byS. pyogenesdCas9. These results provide a roadmap for future engineering efforts to further expand and generalize the scope of bacterial CRISPRa.
Haplotype-based inference of the distribution of fitness effects
Authors: Vecchyo Diego Ortega-Del , Lohmueller Kirk E. , Novembre John 
Published: September 2019

AbstractRecent genome sequencing studies with large sample sizes in humans have discovered a vast quantity of low-frequency variants, providing an important source of information to analyze how selection is acting on human genetic variation. In order to estimate the strength of natural selection acting on low-frequency variants, we have developed a likelihood-based method that uses the lengths of pairwise identity-by-state between haplotypes carrying low-frequency variants. We show that in some non-equilibrium populations (such as those that have had recent population expansions) it is possible to distinguish between positive or negative selection acting on a set of variants. With our new framework, one can infer a fixed selection intensity acting on a set of variants at a particular frequency, or a distribution of selection coefficients for standing variants and new mutations. We apply our method to theUK10Kphased haplotype dataset of 3,781 individuals and find a similar proportion of neutral, moderately deleterious, and deleterious variants compared to previous estimates made using the site frequency spectrum. We discuss several interpretations for this result, including that selective constraints have remained constant over time.
Stochastic sampling provides a unifying account of visual working memory limits
Authors: Schneegans Sebastian , Taylor Robert , Bays Paul M 
Published: September 2019

AbstractResearch into human working memory limits has been shaped by the competition between different formal models, with a central point of contention being whether internal representations are continuous or discrete. Here we describe a sampling approach derived from principles of neural coding as a new framework to understand working memory limits. Reconceptualizing existing models in these terms reveals strong commonalities between seemingly opposing accounts, but also allows us to identify specific points of difference. We show that the discrete versus continuous nature of sampling is not critical to model fits, but that instead random variability in sample counts is the key to reproducing human performance in both single- and whole-report tasks. A probabilistic limit on the number of items successfully retrieved is an emergent property of stochastic sampling, requiring no explicit mechanism to enforce it. These findings resolve discrepancies between previous accounts and establish a unified computational framework for working memory that is compatible with neural principles.
Mental operations in rhythm: motor-to-sensory transformation mediates imagined singing
Authors: Li Yanzhu , Luo Huan , Tian Xing 
Published: September 2019

AbstractWhat enables our mental activities for thinking verbally or humming in our mind? We hypothesized that the interaction between motor and sensory systems induces speech and melodic mental representations, and this motor-to-sensory transformation forms the neural basis that enables our verbal thinking and covert singing. Analogous with the neural entrainment to auditory stimuli, participants imagined singing lyrics of well-known songs rhythmically while their neural electromagnetic signals were recorded using magnetoencephalography (MEG). We found that when participants imagined singing the same song in similar durations across trials, the delta frequency band (1-3 Hz, similar to the rhythm of the songs) showed more consistent phase coherence across trials. This neural phase tracking of imagined singing was observed in a frontal-parietal-temporal network – the proposed motor-to-sensory transformation pathway, including the inferior frontal gyrus (IFG), insula, premotor, intra-parietal sulcus (IPS), the temporal-parietal junction (TPJ), primary auditory cortex (HG), and superior temporal gyrus and sulcus (STG & STS). These results suggest that neural responses can entrain the rhythm of mental activity. Moreover, the theta band (4-8 Hz) phase coherence was localized in the auditory cortices. The mu (9-12 Hz) and beta (17-20 Hz) bands were observed in the right-lateralized sensorimotor systems that were consistent with the singing context. The gamma band was broadly manifested in the observed network. The coherent activation in the motor-to-sensory transformation network as well as the frequency-specific activation in the motor, somatosensory, and auditory cortices mediate the internal construction of perceptual representations and form the foundation of neural computations for mental operations.
Modeling Cancer Genomic Data in Yeast Reveals Selection Against ATM Function During Tumorigenesis
Authors: Hohl Marcel , Mojumdar Aditya , Hailemariam Sarem , Kuryavyi Vitaly , Ghisays Fiorella , Sorenson Kyle , Chang Matthew , Taylor Barry S. , Patel Dinshaw J. , Burgers Peter M. , Cobb Jennifer A. , Petrini John H. J. 
Published: September 2019

AbstractThe DNA damage response (DDR) comprises multiple functions that collectively preserve genomic integrity and suppress tumorigenesis. The Mre11 complex and ATM govern a major axis of the DDR and several lines of evidence implicate that axis in tumor suppression. Components of the Mre11 complex are mutated in approximately five percent of human cancers. Inherited mutations of complex members cause severe chromosome instability syndromes, such as Nijmegen Breakage Syndrome, which is associated with strong predisposition to malignancy. And in mice, Mre11 complex mutations are markedly more susceptible to oncogene-induced carcinogenesis. The complex is integral to all modes of double strand break (DSB) repair and is required for the activation of ATM to effect DNA damage signaling. To understand which functions of the Mre11 complex are important for tumor suppression, we undertook mining of cancer genomic data from the clinical sequencing program at Memorial Sloan Kettering Cancer Center, which includes the Mre11 complex among the 468 genes assessed. Twenty five mutations in MRE11 and RAD50 were modeled in S.cerevisiae and in vitro. The mutations were chosen based on recurrence and conservation between human and yeast. We found that a significant fraction of tumor-borne RAD50 and MRE11 mutations exhibited separation of function phenotypes wherein Tel1/ATM activation was defective while DNA repair functions were mildly or not affected. At the molecular level, the gene products of RAD50 mutations exhibited defects in ATP binding and hydrolysis. The data reflect the importance of Rad50 ATPase activity for Tel1/ATM activation and suggest that inactivation of ATM signaling confers an advantage to burgeoning tumor cells.Author SummaryA complex network of functions is required for suppressing tumorigenesis. These include processes that regulate cell growth and differentiation, processes that repair damage to DNA and thereby prevent cancer promoting mutations and signaling pathways that lead to growth arrest and programmed cell death. The Mre11 complex influences both signaling and DNA repair. To understand its role in tumor suppression, we characterized mutations affecting members of the Mre11 complex that were uncovered through cancer genomic analyses. The data reveal that the signaling functions of the Mre11 complex are important for tumor suppression to a greater degree than its role in DNA repair.
Abuse among elderly living in old age homes of Pokhara Lekhnath Metropolitan City
Authors: Baral Mira Adhikari , Bhagwati KC , Bhandari Pramila 
Published: September 2019

AbstractElder abuse is a common social problem in developed and developing countries and it imposes a huge impact in the physical and mental health of the elderly. With the changes in the socioeconomic aspect of Nepalese society, many elderly are relocating from their homes to old age homes. This study was conducted to assess the status of abuse among the elderly before they enter to old aged homes.A cross sectional study was conducted to assess the status of abuse among elderly before they enter to the old age homes. Consecutive sampling technique was used and semi structured interview schedule was used to collect the data from 109 elderly residing in 6 old aged homes in Pokhara. Collected data was analyzed descriptive and inferential (chi square) statistics using SPSS version 16.The findings from the study showed that that 97.2% of the elderly experienced some forms of abuse before they were brought to the old Age home. Majority of them reported that they experienced neglect (83.5%) followed by verbal abuse (34.9) while least of them (5.5%) reported that they suffered physical abuse(2.8%) and financial abuse(2.8%). However, no significant association could be seen between abuse of elderly with age, education, marital status, place of residence, having children and adequacy of income. It is recommended that the nation develop and implement necessary plans to strengthen the social security of the people at their old age.
Evaluation of rice wild relatives as a source of traits for adaptation to iron toxicity and enhanced grain quality
Authors: Bierschenk Birgit , Tagele Melle Tilahun , Ali Basharat , Ashrafuzzaman Md , Wu Lin-Bo , Becker Matthias , Frei Michael 
Published: September 2019

AbstractRice wild relatives (RWR) constitute an extended gene pool that can be tapped for the breeding of novel rice varieties adapted to abiotic stresses such as iron (Fe) toxicity. Therefore, we screened 75 Oryza genotypes including 16 domesticated O. sativas, one O. glaberrima, and 58 RWR representing 21 species, for tolerance to Fe toxicity. Plants were grown in a semi-artificial greenhouse setup, in which they were exposed either to control conditions, an Fe shock during the vegetative growth stage (acute treatment), or to a continuous moderately high Fe level (chronic treatment). In both stress treatments, foliar Fe concentrations were characteristic of Fe toxicity, and plants developed foliar stress symptoms, which were more pronounced in the chronic Fe stress especially toward the end of the growing season. Among the genotypes that produced seeds, only the chronic stress treatment significantly reduced yields due to increases in spikelet sterility. Moreover, a moderate but non-significant increase in grain Fe concentrations, and a significant increase in grain Zn concentrations were seen in chronic stress. Both domesticated rice and RWR exhibited substantial genotypic variation in their responses to Fe toxicity. Although no RWR strikingly outperformed domesticated rice in Fe toxic conditions, some genotypes scored highly in individual traits. Two O. meridionalis accessions were best in avoiding foliar symptom formation in acute Fe stress, while an O. rufipogon accession produced the highest grain yields in both chronic and acute Fe stress. In conclusion, this study provides the basis for using interspecific crosses for adapting rice to Fe toxicity.
Accuracy of whole-genome sequence imputation using hybrid peeling in large pedigreed livestock populations
Authors: Ros-Freixedes Roger , Whalen Andrew , Chen Ching-Yi , Gorjanc Gregor , Herring William O , Mileham Alan J , Hickey John M 
Published: September 2019

AbstractBackgroundWe demonstrate high accuracy of whole-genome sequence imputation in large livestock populations where only a small fraction of individuals (2%) had been sequenced, mostly at low coverage.MethodsWe used data from four pig populations of different sizes (18,349 to 107,815 individuals) that were broadly genotyped at densities between 15,000 and 75,000 markers genome-wide. Around 2% of the individuals in each population were sequenced (most at 1x or 2x and a small fraction at 30x; average coverage per individual: 4x). We imputed whole-genome sequence with hybrid peeling. We evaluated the imputation accuracy by removing the sequence data of a total of 284 individuals that had been sequenced at high coverage, using a leave-one-out design. We complemented these results with simulated data that mimicked the sequencing strategy used in the real populations to quantify the factors that affected the individual-wise and variant-wise imputation accuracies using regression trees.ResultsImputation accuracy was high for the majority of individuals in all four populations (median individual-wise correlation was 0.97). Individuals in the earliest generations of each population had lower accuracy than the rest, likely due to the lack of marker array data for themselves and their ancestors. The main factors that determined the individual-wise imputation accuracy were the genotyping status of the individual, the availability of marker array data for immediate ancestors, and the degree of connectedness of an individual to the rest of the population, but sequencing coverage had no effect. The main factors that determined variant-wise imputation accuracy were the minor allele frequency and the number of individuals with sequencing coverage at each variant site. These results were validated with the empirical observations.ConclusionsThe coupling of an appropriate sequencing strategy and imputation method, such as described and validated here, is a powerful strategy for generating whole-genome sequence data in large pedigreed populations with high accuracy. This is a critical step for the successful implementation of whole-genome sequence data for genomic predictions and fine-mapping of causal variants.