Miracle-dz/UniFAR-FTUs huggingface dataset:
Experimental Generation of SNP Haplotype Signatures in Patients with Sickle Cell Anaemia

Background Sickle cell anemia is caused by a single type of mutation, a homozygous A→T substitution in the ß globin gene. Clinical severity is diverse, partially due to additional, disease-modifying genetic factors. We are studying one such modifier locus, HMIP (HBS1L-MYB intergenic polymorphism, chromosome 6q23.3). Working with a genetically admixed patient population, we have encountered the necessity to generate haplotype signatures of genetic markers to label genomic fragments with distinct genealogical origin at this locus. With the goal to generate haplotype signatures from patients experimentally, we have investigated the suitability of an existing nanofluidic assay platform to perform phase alignment with single-nucleotide polymorphism alleles. Methodology/Principal Findings Patient DNA samples were loaded onto Fluidigm Digital Arrays and individual DNA molecules were assayed with allele-specific probes for SNP markers. Here we present data showing the utility of the nanofluidic approach, yielding haplotype data identical to those obtained with a family-based method. We then determined haplotype composition in a group of patients with sickle cell disease, including in those where a mathematical inference approach gave ambiguous or misleading results. Experimental phasing of genotypes across 3.8 kb for rs9399137, rs9402685, and rs11759553 created unequivocal haplotype signatures for each of the patients. In 68 patients, we found 8 copies of a haplotype signature (‘C-C-T’), which is known to be prevalent in Europeans but to be absent in West African populations. We have confirmed the identity of our phased allele pairs by single-molecule sequencing and have demonstrated, in principle, that three-allele phasing (using three colors) is a potential extension to this method. Conclusions/Significance Phased haplotypes yield more information than the individual marker genotypes. Procedures such as the one described here would therefore benefit genetic mapping and functional studies as well as diagnostic procedures where the identity or parental origin of short genetic fragments is of importance.
High expression of glycolytic and pigment proteins is associated with worse clinical outcome in stage III melanoma

There are insufficient numbers of prognostic factors available for prediction of clinical outcome in patients with stage III malignant cutaneous melanoma, even when known adverse pathological risk factors, such as macrometastasis, number of lymph node metastases, and ulceration are taken into consideration. The aim of this study was therefore to identify additional prognostic factors to better predict patients with a high risk of relapse, thus enabling us to better determine the need for adjuvant treatment in stage III disease. An RNA oligonucleotide microarray study was performed on first regional lymph node metastases in 42 patients with stage III melanoma: 23 patients with short-term survival (⩽13 months) and 19 with long-term survival (≥60 months), to identify genes associated with clinical outcome. Candidate genes were validated by real-time PCR and immunohistochemical analysis. Several gene ontology (GO) categories were highly significantly differentially expressed including glycolysis (GO: 0006096; P<0.001) and the pigment biosynthetic process (GO: 0046148; P<0.001), in which overexpression was associated with short-disease-specific survival. Three overexpressed glycolytic genes, GAPDHS, GAPDH, and PKM2, and two pigment-related genes, TYRP1 and OCA2, were selected for validation. A significant difference in GAPDHS protein expression between short- and long-term survivors (P=0.021) and a trend for PKM2 (P=0.093) was observed in univariate analysis. Positive expression of at least two of four proteins (GAPDHS, GAPDH, PKM2, TYRP1) in immunohistochemical analysis was found to be an independent adverse prognostic factor for disease-specific survival (P=0.011). Our results indicate that this prognostic panel in combination with established risk factors may contribute to an improved prediction of patients with a high risk of relapse.
Prognostic superiority of daytime ambulatory over conventional blood pressure in four populations: a meta-analysis of 7030 individuals

Objective To investigate the multivariate-adjusted predictive value of systolic and diastolic blood pressures on conventional (CBP) and daytime (10–20 h) ambulatory (ABP) measurement. Methods We randomly recruited 7030 subjects (mean age 56.2 years; 44.8% women) from populations in Belgium, Denmark, Japan and Sweden. We constructed the International Database on Ambulatory blood pressure and Cardiovascular Outcomes. Results During follow-up (median = 9.5 years), 932 subjects died. Neither CBP nor ABP predicted total mortality, of which 60.9% was due to noncardiovascular causes. The incidence of fatal combined with nonfatal cardiovascular events amounted to 863 (228 deaths, 326 strokes and 309 cardiac events). In multivariate-adjusted continuous analyses, both CBP and ABP predicted cardiovascular, cerebrovascular, cardiac and coronary events. However, in fully-adjusted models, including both CBP and ABP, CBP lost its predictive value (P ≥ 0.052), whereas systolic and diastolic ABP retained their prognostic significance (P ≤ 0.007) with the exception of diastolic ABP as predictor of cardiac and coronary events (P ≥ 0.21). In adjusted categorical analyses, normotension was the referent group (CBP < 140/90 mmHg and ABP < 135/85 mmHg). Adjusted hazard ratios for all cardiovascular events were 1.22 [95% confidence interval (CI) = 0.96–1.53; P = 0.09] for white-coat hypertension (≥ 140/90 and < 135/85 mmHg); 1.62 (95% CI = 1.35–1.96; P < 0.0001) for masked hypertension (< 140/90 and ≥ 135/85 mmHg); and 1.80 (95% CI = 1.59–2.03; P < 0.0001) for sustained hypertension (≥ 140/90 and ≥ 135/85 mmHg). Conclusions ABP is superior to CBP in predicting cardiovascular events, but not total and noncardiovascular mortality. Cardiovascular risk gradually increases from normotension over white-coat and masked hypertension to sustained hypertension.
From the Cover: PNAS Plus: Single-molecule imaging reveals target-search mechanisms during DNA mismatch repair

The ability of proteins to locate specific targets among a vast excess of nonspecific DNA is a fundamental theme in biology. Basic principles governing these search mechanisms remain poorly understood, and no study has provided direct visualization of single proteins searching for and engaging target sites. Here we use the postreplicative mismatch repair proteins MutSα and MutLα as model systems for understanding diffusion-based target searches. Using single-molecule microscopy, we directly visualize MutSα as it searches for DNA lesions, MutLα as it searches for lesion-bound MutSα, and the MutSα/MutLα complex as it scans the flanking DNA. We also show that MutLα undergoes intersite transfer between juxtaposed DNA segments while searching for lesion-bound MutSα, but this activity is suppressed upon association with MutSα, ensuring that MutS/MutL remains associated with the damage-bearing strand while scanning the flanking DNA. Our findings highlight a hierarchy of lesion- and ATP-dependent transitions involving both MutSα and MutLα, and help establish how different modes of diffusion can be used during recognition and repair of damaged DNA.
Recent Research on Human Learning Challenges Conventional Instructional Strategies

There has been a recent upsurge of interest in exploring how choices of methods and timing of instruction affect the rate and persistence of learning. The authors review three lines of experimentation—all conducted using educationally relevant materials and time intervals—that call into question important aspects of common instructional practices. First, research reveals that testing, although typically used merely as an assessment device, directly potentiates learning and does so more effectively than other modes of study. Second, recent analysis of the temporal dynamics of learning show that learning is most durable when study time is distributed over much greater periods of time than is customary in educational settings. Third, the interleaving of different types of practice problems (which is quite rare in math and science texts) markedly improves learning. The authors conclude by discussing the frequently observed dissociation between people’s perceptions of which learning procedures are most effective and which procedures actually promote durable learning.
Environmental perturbations lead to extensive directional shifts in RNA processing

Environmental perturbations have large effects on both organismal and cellular traits, including gene expression, but the extent to which the environment affects RNA processing remains largely uncharacterized. Recent studies have identified a large number of genetic variants associated with variation in RNA processing that also have an important role in complex traits; yet we do not know in which contexts the different underlying isoforms are used. Here, we comprehensively characterized changes in RNA processing events across 89 environments in five human cell types and identified 15,300 event shifts (FDR = 15%) comprised of eight event types in over 4,000 genes. Many of these changes occur consistently in the same direction across conditions, indicative of global regulation by trans factors. Accordingly, we demonstrate that environmental modulation of splicing factor binding predicts shifts in intron retention, and that binding of transcription factors predicts shifts in AFE usage in response to specific treatments. We validated the mechanism hypothesized for AFE in two independent datasets. Using ATAC-seq, we found altered binding of 64 factors in response to selenium at sites of AFE shift, including ELF2 and other factors in the ETS family. We also performed AFE QTL mapping in 373 individuals and found an enrichment for SNPs predicted to disrupt binding of the ELF2 factor. Together, these results demonstrate that RNA processing is dramatically changed in response to environmental perturbations through specific mechanisms regulated by trans factors. Author Summary Changes in a cell’s environment and genetic variation have been shown to impact gene expression. Here, we demonstrate that environmental perturbations also lead to extensive changes in alternative RNA processing across a large number of cellular environments that we investigated. These changes often occur in a non-random manner. For example, many treatments lead to increased intron retention and usage of the downstream first exon. We also show that the changes to first exon usage are likely dependent on changes in transcription factor binding. We provide support for this hypothesis by considering how first exon usage is affected by disruption of binding due to treatment with selenium. We further validate the role of a specific factor by considering the effect of genetic variation in its binding sites on first exon usage. These results help to shed light on the vast number of changes that occur in response to environmental stimuli and will likely aid in understanding the impact of compounds to which we are daily exposed.
Isolated populations of a rare alpine plant show high genetic diversity and considerable population differentiation.

BACKGROUND AND AIMS Gene flow and genetic variability within and among alpine plant populations can be greatly influenced by the steep environmental gradients and heterogeneous topography of alpine landscapes. In this study, the effects are examined of natural isolation of alpine habitats on genetic diversity and geographic structure in populations of C. thyrsoides, a rare and isolated European Alpine monocarpic perennial with limited seed dispersal capacity. METHODS Molecular diversity was analysed for 736 individuals from 32 populations in the Swiss Alps and adjacent Jura mountains using five polymorphic microsatellite loci. Pollen flow was estimated using pollen grain-sized fluorescent powder. In addition, individual-based Bayesian approaches were applied to examine population structure. KEY RESULTS High within-population genetic diversity (H(E) = 0.76) and a relatively low inbreeding coefficient (F(IS) = 0.022) were found. Genetic differentiation among populations measured with a standardized measure was considerable (G'(ST) = 0.53). A significant isolation-by-distance relationship was found (r = 0.62, P < 0.001) and a significant geographic sub-structure, coinciding with proposed postglacial migration patterns. Altitudinal location and size of populations did not influence molecular variation. Direct measures of pollen flow revealed that insect-mediated pollen dispersal was restricted to short distances within a population. CONCLUSIONS The natural isolation of suitable habitats for C. thyrsoides restricts gene flow among the populations as expected for a monocarpic species with very limited seed dispersal capacities. The observed high within-population genetic diversity in this rare monocarpic perennial is best explained by its outcrossing behaviour, long-lived individuals and overlapping generations. Despite the high within-population genetic diversity, the considerable genetic differentiation and the clear western-eastern differentiation in this species merits consideration in future conservation efforts.
Polyamide-6 composites reinforced with cellulose fibers and fabricated by extrusion: Effect of fiber bleaching on mechanical properties and stability

We prepared polyamide-6 (PA-6) composites using bleached and semibleached cellulose fibers from Eucalyptus species by processing in a corotating interpenetrating twin-screw extruder. PA-6 is a challenging matrix because of its high processing temperature, which overlaps the thermodegradation temperature of the fibers. The selection of the processing conditions for extrusion and the use of the lubricant ethylene bis (stearamide) permitted the production of composites with 20, 30, and 40 wt% of bleached fibers, which are lighter than the corresponding glass fiber composites. Composites with 30 wt% of bleached fibers yield the best mechanical properties and good fiber/matrix interaction, as demonstrated by mechanical tests and scanning electron microscopy. X-ray photoelectron spectroscopy studies showed that the natural moisture in the fibers promotes the fiber/matrix interaction through the formation of ester bonds. We assessed the effect caused by the presence of lignin in the fibers. Composites containing 30 wt% of semibleached fibers maintained the flexural properties and showed small improvements in thermal stability when compared with bleached fiber composites; however, there is a slight decrease in the tensile properties. Through accelerated aging tests, we observed that increased lignin concentration in the fibers reduced the formation of carbonyl compounds on sample surfaces, indicating a stabilization effect. POLYM. COMPOS. , 2015. © 2015 Society of Plastics Engineers
Emissions of C6–C8 aromatic compounds in the United States: Constraints from tall tower and aircraft measurements

We present two full years of continuous C6–C8 aromatic compound measurements by PTR‐MS at the KCMP tall tower (Minnesota, US) and employ GEOS‐Chem nested grid simulations in a Bayesian inversion to interpret the data in terms of new constraints on US aromatic emissions. Based on the tall tower data, we find that the RETRO inventory (year‐2000) overestimates US C6–C8 aromatic emissions by factors of 2.0–4.5 during 2010–2011, likely due in part to post‐2000 reductions. Likewise, our implementation of the US EPA's NEI08 overestimates the toluene flux by threefold, reflecting an inventory bias in non‐road emissions plus uncertainties associated with species lumping. Our annual top‐down emission estimates for benzene and C8 aromatics agree with the NEI08 bottom‐up values, as does the inferred contribution from non‐road sources. However, the NEI08 appears to underestimate on‐road emissions of these compounds by twofold during the warm season. The implied aromatic sources upwind of North America are more than double the prior estimates, suggesting a substantial underestimate of East Asian emissions, or large increases there since 2000. Long‐range transport exerts an important influence on ambient benzene over the US: on average 43% of its wintertime abundance in the US Upper Midwest is due to sources outside North America. Independent aircraft measurements show that the inventory biases found here for C6–C8 aromatics also apply to other parts of the US, with notable exceptions for toluene in California and Houston, Texas. Our best estimates of year‐2011 contiguous US emissions are 206 (benzene), 408 (toluene), and 822 (C8 aromatics) GgC.
Escherichia coli DNA helicases: mechanisms of DNA unwinding

DNA helicases are ubiquitous enzymes that catalyse the unwinding of duplex DNA during replication, recombination and repair. These enzymes have been studied extensively; however, the specific details of how any helicase unwinds duplex DNA are unknown. Although it is clear that not all helicases unwind duplex DNA in an identical way, many helicases possess similar properties, which are thus likely to be of general importance to their mechanism of action. For example, since helicases appear generally to be oligomeric enzymes, the hypothesis is presented in this review that the functionally active forms of DNA helicases are oligomeric. The oligomeric nature of helicases provides them with multiple DNA‐binding sites, allowing the transient formation of ternary structures, such that at an unwinding fork, the helicase can bind either single‐stranded and duplex DNA simultaneously or two strands of single‐stranded DNA. Modulation of the relative affinities of these binding sites for single‐stranded versus duplex DNA through ATP binding and hydrolysis would then provide the basis for a cycling mechanism for processive unwinding of DNA by helicases. The properties of the Escherichia coli DNA helicases are reviewed and possible mechanisms by which helicases might unwind duplex DNA are discussed in view of their oligomeric structures, with emphasis on the E. coli Rep, RecBCD and phage T7 gene 4 helicases.
A Unifying Perspective on the Quasi-steady Analysis of Magnetorheological Dampers

A magnetorheological (MR) fluid, modeled as a Bingham plastic (BP) material, is characterized by a field dependent yield stress, and a (nearly constant) postyield plastic viscosity. Based on viscometric measurements, such a BP model is an idealization to physical MR behavior, albeit a useful one. A better approximation involves modifying both the preyield and postyield constitutive behavior as follows: (1) assume a high viscosity preyield behavior when the shear stress is less than the transition stress, and (2) assume a power law fluid (i.e., strain rate dependent viscosity) when the shear stress is greater than the transition stress. Assuming a power law fluid in postyield allows the model to account for shear thinning behavior exhibited by MR fluids at higher strain rates. Such an idealization for MR fluid constitutive behavior is called an viscous-power law model, or a Herschel—Bulkley (HB) model with preyield viscosity. This study develops a quasi-steady analysis for such a constitutive MR fluid behavior applied to an MR flow mode damper. Closed form solutions are developed for the fluid velocity, as well as key performance metrics, such as damping capacity and dynamic range (ratio of field-on to field-off force). For the given fluid properties and flow mode damper geometry, the fluid velocity profile and gradient, and the relationship of the damper force and piston velocity are analyzed. In addition, specializations to existing models, such as the HB, biviscous, and BP models, are shown to be easily captured by this model when physical constraints (idealizations) are placed on the rheological behavior of the MR fluid.
Maximally Non-Local and Monogamous Quantum Correlations

We introduce a version of the chained Bell inequality for an arbitrary number of measurement outcomes and use it to give a simple proof that the maximally entangled state of two d-dimensional quantum systems has no local component. That is, if we write its quantum correlations as a mixture of local correlations and general (not necessarily quantum) correlations, the coefficient of the local correlations must be zero. This suggests an experimental program to obtain as good an upper bound as possible on the fraction of local states and provides a lower bound on the amount of classical communication needed to simulate a maximally entangled state in dxd dimensions. We also prove that the quantum correlations violating the inequality are monogamous among nonsignaling correlations and, hence, can be used for quantum key distribution secure against postquantum (but nonsignaling) eavesdroppers.
An Attachment to the Constant Rate of Elongation Tester for Estimating Surface Irregularities of Fabrics

Fabric surface irregularities are measured using a novel attachment to a constant rate of elongation tester. The number of peaks and amplitude of the stick-slip traces correspond to the number and height of surface asperities on fabrics, respectively. Fabrics that yield more peaks and lower amplitude pulses are judged smoother than those with fewer peaks and higher amplitudes.
Understanding Free/Open Source Software Development Processes

This article introduces a special issue of Software Process—Improvement and Practice focusing on processes found in free or open source software development (F/OSSD) projects. It seeks to provide a background overview of research in this area through a review of selected empirical studies of F/OSSD processes. The results and findings from a survey of empirical studies of F/OSSD give rise to an interesting variety of opportunities and challenges for understanding these processes, which are identified along the way. Overall, what becomes clear is that studies of F/OSSD processes reveal a more diverse set of different types of processes than have typically been examined in conventional software development projects. The articles in this special issue further advance understanding of what processes characterize and shape F/OSSD. Copyright © 2006 John Wiley & Sons, Ltd.