A geometric approach to visualization of variability in functional data

We propose a new method for the construction and visualization of boxplot-type displays for functional data. We use a recent functional data analysis framework, based on a representation of functions called square-root slope functions, to decompose observed variation in functional data into three main components: amplitude, phase, and vertical translation. We then construct separate displays for each component, using the geometry and metric of each representation space, based on a novel definition of the median, the two quartiles, and extreme observations. The outlyingness of functional data is a very complex concept. Thus, we propose to identify outliers based on any of the three main components after decomposition. We provide a variety of visualization tools for the proposed boxplot-type displays including surface plots. We evaluate the proposed method using extensive simulations and then focus our attention on three real data applications including exploratory data analysis of sea surface temperature functions, electrocardiogram functions and growth curves

The microRNA-29 family in cartilage homeostasis and osteoarthritis

MicroRNAs have been shown to function in cartilage development and homeostasis, as well as in progression of osteoarthritis. The objective of the current study was to identify microRNAs involved in the onset or early progression of osteoarthritis and characterise their function in chondrocytes. MicroRNA expression in mouse knee joints post-DMM surgery was measured over 7 days. Expression of miR-29b-3p was increased at day 1 and regulated in the opposite direction to its potential targets. In a mouse model of cartilage injury and in end-stage human OA cartilage, the miR-29 family were also regulated. SOX9 repressed expression of miR-29a-3p and miR-29b-3p via the 29a/b1 promoter. TGFβ1 decreased expression of miR-29a, b and c (3p) in primary chondrocytes, whilst IL-1β increased (but LPS decreased) their expression. The miR-29 family negatively regulated Smad, NFκB and canonical WNT signalling pathways. Expression profiles revealed regulation of new WNT-related genes. Amongst these, FZD3, FZD5, DVL3, FRAT2, CK2A2 were validated as direct targets of the miR-29 family. These data identify the miR-29 family as microRNAs acting across development and progression of OA. They are regulated by factors which are important in OA and impact on relevant signalling pathways

Genetic analysis of haemophilia A in Bulgaria

BACKGROUND: Haemophilias are the most common hereditary severe disorders of blood clotting. In families afflicted with heamophilia, genetic analysis provides opportunities to prevent recurrence of the disease. This study establishes a diagnostical strategy for carriership determination and prenatal diagnostics of haemophilia A in Bulgarian haemophilic population. METHODS: A diagnostical strategy consisting of screening for most common mutations in the factor VIII gene and analysis of a panel of eight linked to the factor VIII gene locus polymorphisms was established. RESULTS: Polymorphic analysis for carrier status determination of haemophilia A was successful in 30 families out of 32 (94%). Carrier status was determined in 25 of a total of 28 women at risk (89%). Fourteen prenatal diagnoses in women at high risk of having a haemophilia A – affected child were performed, resulting in 6 healthy boys and 5 girls. CONCLUSION: The compound approach proves to be a highly informative and cost-effective strategy for prevention of recurrence of haemophilia A in Bulgaria. DNA analysis facilitates carriership determination and subsequent prenatal diagnosis in the majority of Bulgarian families affected by haemophilia A

Regulation of the IGFBP-5 and MMP-13 genes by the microRNAs miR-140 and miR-27a in human osteoarthritic chondrocytes

<p>Abstract</p> <p>Background</p> <p>MMP-13 and IGFBP-5 are important factors involved in osteoarthritis (OA). We investigated whether two highly predicted microRNAs (miRNAs), miR-140 and miR-27a, regulate these two genes in human OA chondrocytes.</p> <p>Methods</p> <p>Gene expression was determined by real-time PCR. The effect of each miRNA on IGFBP-5 and MMP-13 expression/production was evaluated by transiently transfecting their precursors (pre-miRNAs) and inhibitors (anti-miRNAs) into human OA chondrocytes. Modulation of IGFBP-5, miR-140 and miR-27a expression was determined upon treatment of OA chondrocytes with cytokines and growth factors.</p> <p>Results</p> <p>IGFBP-5 was expressed in human chondrocytes with its level significantly lower (p < 0.04) in OA. Five computational algorithms identified miR-140 and miR-27a as possible regulators of MMP-13 and IGFBP-5 expression. Data showed that both miRNAs were expressed in chondrocytes. There was a significant reduction (77%, p < 0.01) in miR-140 expression in OA compared to the normal chondrocytes, whereas miR-27a expression was only slightly decreased (23%). Transfection with pre-miR-140 significantly decreased (p = 0.0002) and with anti-miR-140 significantly increased (p = 0.05) IGFBP-5 expression at 24 hours, while pre-miR-27a did not affect either MMP-13 or IGFBP-5. Treatment with anti-miR-27a, but not with anti-miR-140, significantly increased the expression of both MMP-13 (p < 0.05) and IGFBP-5 (p < 0.01) after 72 hours of incubation. MMP-13 and IGFBP-5 protein production followed the same pattern as their expression profile. These data suggest that IGFBP-5 is a direct target of miR-140, whereas miR-27a down-regulates, likely indirectly, both MMP-13 and IGFBP-5.</p> <p>Conclusion</p> <p>This study is the first to show the regulation of these miRNAs in human OA chondrocytes. Their effect on two genes involved in OA pathophysiology adds another level of complexity to gene regulation, which could open up novel avenues in OA therapeutic strategies.</p

Remembering the Sea: Personal and Communal Recollections of Maritime Life in Jizan and the Farasan Islands, Saudi Arabia

This is the final version of the article. Available from the publisher via the DOI in this record.People create narratives of their maritime past through the remembering and forgetting of seafaring experiences, and through the retention and disposal of maritime artefacts that function mnemonically to evoke or suppress those experiences. The sustenance and reproduction of the resulting narratives depends further on effective media of intergenerational transmission; otherwise, they are lost. Rapid socio-economic transformation across Saudi Arabia in the age of oil has disrupted longstanding seafaring economies in the Red Sea archipelago of the Farasan Islands, and the nearby mainland port of Jizan. Vestiges of wooden boatbuilding activity are few; long-distance dhow trade with South Asia, the Arabian-Persian Gulf and East Africa has ceased; and a once substantial pearling and nacre (mother of pearl) collection industry has dwindled to a tiny group of hobbyists: no youth dive today. This widespread withdrawal from seafaring activity among many people in these formerly maritime-oriented communities has diminished the salience of such activity in cultural memory, and has set in motion narrative creation processes, through which memories are filtered and selected, and objects preserved, discarded, or lost. This paper is a product of the encounter of the authors with keepers of maritime memories and objects in the Farasan Islands and Jizan. An older generation of men recall memories of their experiences as boat builders, captains, seafarers, pearl divers and fishermen. Their recounted memories are inscribed, and Arabic seafaring terms recorded. The extent of the retention of maritime material cultural items as memorials is also assessed, and the rôle of individual, communal and state actors in that retention is considered. Through this reflection, it becomes clear that the extra-biological memory and archive of the region’s maritime past is sparse; that intergenerational transmission is failing; that the participation of state agencies in maritime heritage creation is highly limited; and that, as a result, memories current among the older generation have limited prospect of survival. These memories, recorded and interpreted here, identify the Farasan Islands as a former centre of the pearling industry in the Red Sea, and identify them and Jizan as open to far-reaching maritime-mediated cultural influences in an era before the imposition of the attributes of the modern nation-state.This study was funded by the Golden Web Foundation (UK registered charity number 1100608), with additional support from the Seven Pillars of Wisdom Trust (UK registered charity number 208669)

Transcriptome-Wide Prediction of miRNA Targets in Human and Mouse Using FASTH

Transcriptional regulation by microRNAs (miRNAs) involves complementary base-pairing at target sites on mRNAs, yielding complex secondary structures. Here we introduce an efficient computational approach and software (FASTH) for genome-scale prediction of miRNA target sites based on minimizing the free energy of duplex structure. We apply our approach to identify miRNA target sites in the human and mouse transcriptomes. Our results show that short sequence motifs in the 5′ end of miRNAs frequently match mRNAs perfectly, not only at validated target sites but additionally at many other, energetically favourable sites. High-quality matching regions are abundant and occur at similar frequencies in all mRNA regions, not only the 3′UTR. About one-third of potential miRNA target sites are reassigned to different mRNA regions, or gained or lost altogether, among different transcript isoforms from the same gene. Many potential miRNA target sites predicted in human are not found in mouse, and vice-versa, but among those that do occur in orthologous human and mouse mRNAs most are situated in corresponding mRNA regions, i.e. these sites are themselves orthologous. Using a luciferase assay in HEK293 cells, we validate four of six predicted miRNA-mRNA interactions, with the mRNA level reduced by an average of 73%. We demonstrate that a thermodynamically based computational approach to prediction of miRNA binding sites on mRNAs can be scaled to analyse complete mammalian transcriptome datasets. These results confirm and extend the scope of miRNA-mediated species- and transcript-specific regulation in different cell types, tissues and developmental conditions

Is Happiness a trait?

ABSTRACT One of the ideological foundations of the modern welfare states is the belief that people can be made happier by providing them with better living conditions. This belief is challenged by the theory that happiness is a fixed 'trait', rather than a variable 'state'. This theory figures both at the individual level and at the societal level. The individual level variant depicts happiness as an aspect of personal character; rooted in inborn temperament or acquired disposition. The societal variant sees happiness as a matter of national character; embedded in shared values and beliefs. Both variants imply that a better society makes no happier people. Happiness can be regarded as a trait if it meets three criteria: 1) temporal stability, 2) cross-situational consistency, and 3) inner causation. This paper checks whether that is, indeed, the case. The theory that happiness is a personal-character-trait is tested in a (meta) analysis of longitudinal studies. The results are: 1) Happiness is quite stable on the short term, but not in the long run, neither relatively nor absoloutely. 2) Happiness is not insensitive to fortune or adversity. 3) Happiness is not entirely built-in: its genetic basis is at best modest and psychological factors explain only part of its variance. The theory that happiness is a national-character-trait is tested in an analysis of differences in average happiness between nations. The results point in the same direction: 1) Though generally fairly stable over the last decades, nation-happiness has changed profoundly in some cases both absolutely and relatively. 2) Average happiness in nations is clearly not indep

Bayesian Analysis of Curves Shape Variation Through Registration and Regression

This manuscript reviews the use of Bayesian hierarchical curve registration in Biostatistics and Bioinformatics.Several models allowing for unit-specific random time scales are discussed and applied to longitudinal dataarising in biomedicine, pharmacokinetics and time-course genomics. We consider representations of random functionals based on P-spline priors. Under this framework, straightforward posterior simulation strategies are outlined for inference.Beyond curve registration, we discuss jointregression modeling of both random effects and population level functional quantities. Finally, the use of mixture priors is discussed in the setting of differential expression analysis

Pre-Micro RNA Signatures Delineate Stages of Endothelial Cell Transformation in Kaposi Sarcoma

MicroRNAs (miRNA) have emerged as key regulators of cell lineage differentiation and cancer. We used precursor miRNA profiling by a novel real-time QPCR method (i) to define progressive stages of endothelial cell transformation cumulating in Kaposi sarcoma (KS) and (ii) to identify specific miRNAs that serve as biomarkers for tumor progression. We were able to compare primary patient biopsies to well-established culture and mouse tumor models. Loss of mir-221 and gain of mir-15 expression demarked the transition from merely immortalized to fully tumorigenic endothelial cells. Mir-140 and Kaposi sarcoma–associated herpesvirus viral miRNAs increased linearly with the degree of transformation. Mir-24 emerged as a biomarker specific for KS