Miracle-dz/UniFAR-FTUs huggingface dataset:
Genetic association of COL5A1 variants in keratoconus patients suggests a complex connection between corneal thinning and keratoconus.

PURPOSE Single nucleotide polymorphisms (SNPs) located near or within the COL5A1 gene, at 9q34.2-q34.3 chromosomal region have been reported in association with central corneal thickness (CCT). Using family linkage analysis, we identified a keratoconus susceptibility locus at 9q34. These findings led us to perform an association study between COL5A1 variation and keratoconus susceptibility. METHODS A Caucasian case-control cohort of 222 keratoconus patients and 3324 controls was selected as the discovery panel. An independent case-control panel of 304 cases and 518 controls and a family panel of 186 subjects were replicated for genotyping and association. Forty-four SNPs (21 for discovery and 23 for fine-mapping) spanning 300 kilobases in and around COL5A1 were genotyped and tested for genetic association. Logistic regression models implemented in PLINK were used to test for association in case controls. Generalized estimating equation models accounting for familial correlations implemented in genome-wide interaction analyses with family data were used for association testing in families. RESULTS Two CCT associated SNPs (rs1536482 and rs7044529 near and within COL5A1) were identified in the keratoconus discovery cohort (P values of 6.5 × 10(-3) and 7.4 × 10(-3)). SNP rs1536482 was replicated in the second case-control sample (P = 0.02), and SNP rs7044529 was replicated in a keratoconus family panel (P = 0.03). Meta P values of rs1536482 and rs7044529 in the keratoconus cohorts were 1.5 × 10(-4) (odds ratio [OR] = 1.30) and 2.9 × 10(-3) (OR = 1.39). After Bonferroni correction, the association of SNP rs1536482 remained significant (P = 6.5 × 10(-3)). CONCLUSIONS SNPs in the COL5A1 region, which regulate normal variation in CCT, may play a role in the thinning associated with keratoconus.
Experimental Evidence for a Reduced Metal-saturated Upper Mantle

The uppermost mantle as sampled by xenoliths, peridotite massifs and primitive basaltic melts appears to be relatively oxidized, with oxygen fugacities between the magnetite^wu« stite and fayalite^ferrosilite^magnetite equilibria.Whether this range in oxygen fugacity is a shallow mantle signature or representative of the entire upper mantle still is unclear and a matter of debate because mantle regions deeper than 200 km are not well sampled. To constrain the redox state of the deeper upper mantle, we performed experiments from 1 to 14 GPa and 1220 to 16508C on a model peridotite composition, encompassing the convecting asthenospheric mantle down to the Transition Zone at 410 km depth.The experiments were run in iron metal capsules to buffer fO2 close to an oxygen fugacity about 0·5 log units below the iron^wu« stite equilibrium. Analysis of the experimental phases for ferric iron using electron energy loss spectroscopy reveals that at pressures higher than 7 GPa, subcalcic pyroxene and majoritic garnet incorporate appreciable amounts of ferric iron, even though at the experimental conditions they were in redox equilibrium with metallic iron. The major ferric iron carrier in the upper mantle is majoritic garnet, followed by subcalcic pyroxene. At around 8 1GPa, corresponding to 250 30 km depth in the upper mantle, sufficient quantities of subcalcic pyroxene and majoritic garnet are stabilized that all the ferric iron thought to be present in fertile upper mantle (i.e. 2000 ppm) can be accommodated in solid solution in these phases, even though they were synthesized in redox equilibrium with metallic Fe. Based on the results of the experiments, it can be stated that, on a global scale, an oxidized upper mantle near the fayalite^ferrosilite^magnetite equilibrium is the exception rather than the rule. More than 75 vol. % of the Earth’s present-day mantle is likely to be saturated with metallic iron.
QoS-Driven Selection of Web Services for Transactional Composition

Web services composition has been gaining interest over the last years as it leverages the capabilities to offer complex operations resulting from the aggregation of Web services offered by different organizations. As composite Web services are often long-running, loosely coupled and cross-organizational applications, advanced transactional support is required to ensure reliable execution. In addition, in the presence of multiple Web services with equivalent functionality, users will discriminate the alternatives based on their quality of service (QoS). This paper address the issue of selecting and composing Web services not only according to their functional requirements but also to their transactional properties and QoS characteristics defined using a quality model. In this model, Web services are selected in a way that satisfies user preferences. These preferences are expressed as weights over QoS criterion and as risk level defining semantically the transactional requirements.
On the Use of Context-Dependent Modeling Units for HMM-Based Offline Handwriting Recognition

The use of context dependent modeling units in handwriting recognition has been considered by many authors as promising substantial performance improvements in systems based on Hidden-Markov models. Interestingly, in the literature only a few approaches limited to online recognition are documented to make use of this technology. Therefore, we investigated whether context dependent modeling also offers advantages for offline recognition systems. The moderate performance improvements we achieved on a challenging unconstrained handwriting recognition task suggest that context dependent modeling can not easily be exploited for offline recognition. In this paper we will present the principles behind context dependent modeling and discuss the reasons for its limited applicability in recognizing offline handwriting data.
Critical Residues within the BTB Domain of PLZF and Bcl-6 Modulate Interaction with Corepressors

ABSTRACT The PLZF (promyelocytic leukemia zinc finger) transcriptional repressor, when fused to retinoic acid receptor alpha (RARα), causes a refractory form of acute promyelocytic leukemia. The highly conserved N-terminal BTB (bric a brac, tramtrack, broad complex)/POZ domain of PLZF plays a critical role in this disease, since it is required for transcriptional repression by the PLZF-RARα fusion protein. The crystal structure of the PLZF BTB domain revealed an obligate homodimer with a highly conserved charged pocket formed by apposition of the two monomers. An extensive structure-function analysis showed that the charged pocket motif plays a major role in transcriptional repression by PLZF. We found that mutations of the BTB domain that neutralize key charged pocket residues did not disrupt dimerization, yet abrogated the ability of PLZF to repress transcription and led to the loss of interaction with N-CoR, SMRT, and histone deacetylases (HDACs). We extended these studies to the Bcl-6 protein, which is linked to the pathogenesis of non-Hodgkin's lymphomas. In this case, neutralizing the charged pocket also resulted in loss of repression and corepressor binding. Experiments with purified protein showed that corepressor-BTB interactions were direct. A comparison of the PLZF, Bcl-6, and the FAZF (Fanconi anemia zinc finger)/ROG protein shows that variations in the BTB pocket result in differential affinity for corepressors, which predicts the potency of transcriptional repression. Thus, the BTB pocket represents a molecular structure involved in recruitment of transcriptional repression complexes to target promoters.
System wide analyses have underestimated protein abundances and the importance of transcription in mammals

Large scale surveys in mammalian tissue culture cells suggest that the protein expressed at the median abundance is present at 8,000–16,000 molecules per cell and that differences in mRNA expression between genes explain only 10–40% of the differences in protein levels. We find, however, that these surveys have significantly underestimated protein abundances and the relative importance of transcription. Using individual measurements for 61 housekeeping proteins to rescale whole proteome data from Schwanhausser et al. (2011), we find that the median protein detected is expressed at 170,000 molecules per cell and that our corrected protein abundance estimates show a higher correlation with mRNA abundances than do the uncorrected protein data. In addition, we estimated the impact of further errors in mRNA and protein abundances using direct experimental measurements of these errors. The resulting analysis suggests that mRNA levels explain at least 56% of the differences in protein abundance for the 4,212 genes detected by Schwanhausser et al. (2011), though because one major source of error could not be estimated the true percent contribution should be higher. We also employed a second, independent strategy to determine the contribution of mRNA levels to protein expression. We show that the variance in translation rates directly measured by ribosome profiling is only 12% of that inferred by Schwanhausser et al. (2011), and that the measured and inferred translation rates correlate poorly (R2 = 0.13). Based on this, our second strategy suggests that mRNA levels explain ∼81% of the variance in protein levels. We also determined the percent contributions of transcription, RNA degradation, translation and protein degradation to the variance in protein abundances using both of our strategies. While the magnitudes of the two estimates vary, they both suggest that transcription plays a more important role than the earlier studies implied and translation a much smaller role. Finally, the above estimates only apply to those genes whose mRNA and protein expression was detected. Based on a detailed analysis by Hebenstreit et al. (2012), we estimate that approximately 40% of genes in a given cell within a population express no mRNA. Since there can be no translation in the absence of mRNA, we argue that differences in translation rates can play no role in determining the expression levels for the ∼40% of genes that are non-expressed.
Latent infection of human cytomegalovirus is associated with the development of gastric cancer

The worldwide contagion, human cytomegalovirus (HCMV), may cause a series of disorders in infected individuals. The aim of the present study was to investigate whether HCMV infection is associated with the development of gastric cancer. In this study, the positive expression of unique long (UL)133-UL138 and immediate-early (IE)1 genes, which are associated with viral latency and replication, respectively, were detected using nested polymerase chain reaction. A χ2 test and logistic regression analysis were performed to further investigate the preliminary data. The data indicated that the positive rate of UL133, UL135 and UL136 expression in cancer tissues was higher than that in paired normal tissues (P=0.01, 0.027 and 0.013, respectively). However, no significant differences were identified in the UL133–138 locus and IE1 gene when associated with clinicopathological features. Furthermore, seven infection patterns were identified, with the UL133 + UL138 infection pattern representing the largest proportion in the cancer (60.34%) and normal tissues (42.11%). In conclusion, it is possible that the UL133–UL138 locus is important in the occurrence of gastric cancer. The mechanism by which UL133–UL138 locus expression differs in human gastric cancer requires further investigation.
Association between Diabetes Mellitus and Oral Health Status in Japanese Adults

AimThe objective of this study was to analyze the oral health among Japanese adults, with and without diabetes mellitus.MethodologyThe subjects were 518 community residents aged 20 to 91 years in Japan, who participated in the “Akita health and nutrition survey” and the “Akita dental disease survey”, conducted in 2006. The surveys comprised a self‐administered questionnaire, along with medical and dental examinations.ResultsUsing the community periodontal index (CPI), the mean numbers of sextants presenting codes 0, 1 and 2 were significantly lower in diabetics than non‐diabetics among the 59 years or younger age group. Although the mean numbers of sextants with codes 0, 1 and 2 among the 60 to 69 years age group were lower, and sextants with a code X among the 59 years or younger age group were higher in diabetics than non‐diabetics, no statistically significant differences were detected. The tendency of lower mean numbers of natural teeth and functional tooth units in diabetics than non‐diabetics was observed, however no differences were statistically significant.ConclusionThe outcome of periodontal disease seemed to be influenced by the diabetic state to some degree, but a clear association between diabetes and oral health status was not found.
Estimating Earnings Adjustment Frictions: Method and Evidence from the Social Security Earnings Test

We study frictions in adjusting earnings in response to changes in the Social Security Annual Earnings Test (AET), using a panel of Social Security Administration microdata on one percent of the U.S. population from 1961 to 2006. Individuals continue to "bunch" at the convex kink the AET creates even when they are no longer subject to the AET, demonstrating that adjustment frictions help drive behavior in a new and important context. We develop a novel framework for estimating an earnings elasticity and an adjustment cost using information on the amount of bunching at kinks before and after policy changes in earnings incentives around the kinks. We apply this method in settings in which individuals face changes in the AET benefit reduction rate, and we estimate in a baseline case that the earnings elasticity with respect to the implicit net-of-tax share is 0.23, and the fixed cost of adjustment is $152.08. Our results demonstrate that the short-run impact of changes in the effective marginal tax rate can be substantially attenuated.
Semi-automated discovery of application session structure

While the problem of analyzing network traffic at the granularity of individual connections has seen considerable previous work and tool development, understanding traffic at a higher level - the structure of user-initiated sessions comprised of groups of related connections - remains much less explored. Some types of session structure, such as the coupling between an FTP control connection and the data connections it spawns, have prespecified forms, though the specifications do not guarantee how the forms appear in practice. Other types of sessions, such as a user reading email with a browser, only manifest empirically. Still other sessions might exist without us even knowing of their presence, such as a botnet zombie receiving instructions from its master and proceeding in turn to carry them out. We present algorithms rooted in the statistics of Poisson processes that can mine a large corpus of network connection logs to extract the apparent structure of application sessions embedded in the connections. Our methods are semi-automated in that we aim to present an analyst with high-quality information (expressed as regular expressions) reflecting different possible abstractions of an application's session structure. We develop and test our methods using traces from a large Internet site, finding diversity in the number of applications that manifest, their different session structures, and the presence of abnormal behavior. Our work has applications to traffic characterization and monitoring, source models for synthesizing network traffic, and anomaly detection.
The Effect of Wettability Heterogeneity on Relative Permeability of Two‐Phase Flow in Porous Media: A Lattice Boltzmann Study

Relative permeability is a critical parameter characterizing multiphase flow in porous media and it is strongly dependent on the wettability. In many situations, the porous media are nonuniformly wet. To investigate the effect of wettability heterogeneity on relative permeability of two‐phase flow in porous media, a multi‐relaxation‐time color‐gradient lattice Boltzmann model is adopted to simulate oil/water two‐phase flow in porous media with different oil‐wet solid fractions. For the water phase, when the water saturation is high, the relative permeability of water increases with the increase of oil‐wet solid fraction under a constant water saturation. However, as the water saturation decreases to an intermediate value (about 0.4–0.7), the relative permeability of water in fractionally wet porous media could be lower than that in purely water‐wet porous media, meaning additional flow resistance exists in the fractionally wet porous media. For the oil phase, similar phenomenon is observed. This phenomenon is mainly caused by the wettability‐related microscale fluid distribution. According to both our simulation results and theoretical analysis, it is found that the relative permeability of two‐phase flow in porous media is strongly related to three parameters: the fluid saturation, the specific interfacial length of fluid, and the fluid tortuosity in the flow direction. The relationship between the relative permeability and these parameters under different capillary numbers is explored in this paper.
Investigating and modelling rationale style arguments

This thesis investigates how the intended direction (either self or other) and perception of future use when constructing a rationale style argument can impact upon decision confidence and argument quality (in terms of rhetorical structure and the use of rebuttals). The literature review reveals emerging needs for further understanding of how the perception held of intended rationale direction can impact on the attitudes held about the decision and structure of the rationale. Rationale style arguments were the focus of investigation due to their prevalence in research, potentially rich and varied argumentative structures and wide scope of utility in other domains. The findings inform a rationale style argument model that assists in scoping the argument context, adding further dimensions including the intended direction of the rationale (self or other) and argument competency. The thesis proposes two new frameworks that offer a semi-automated solution to argument quality analysis. A good level of agreement between the new quality analysis frameworks and the original Toulmin based quality scheme used was found and the utility of the findings for future feedback tools and online argument analysis is discussed. The new semi-automated frameworks would enable analyses to be carried out rapidly and with less subjective judgement. The work may also have applications for educational tool designs that seek to incorporate argument analysis and feedback on text based arguments.
Pharmacological comparison of swelling‐activated excitatory amino acid release and Cl− currents in cultured rat astrocytes

Ubiquitously expressed volume‐regulated anion channels (VRACs) are chloride channels which are permeable to a variety of small organic anions, including the excitatory amino acids (EAAs) glutamate and aspartate. Broad spectrum anion channel blockers strongly reduce EAA release in cerebral ischaemia and other pathological states associated with prominent astrocytic swelling. However, it is uncertain whether VRAC serves as a major pathway for EAA release from swollen cells. In the present study, we measured swelling‐activated release of EAAs as d‐[3H]aspartate efflux, and VRAC‐mediated Cl− currents by whole‐cell patch clamp in cultured rat astrocytes. We compared the pharmacological profiles of the swelling‐activated EAA release pathway and Cl− currents. The expression of candidate Cl− channels was confirmed by RT‐PCR. The maxi Cl− channel (p‐VDAC) blocker Gd3+, the ClC‐2 inhibitor Cd2+, and the MDR‐1 blocker verapamil did not affect EAA release or VRAC currents. An antagonist of calcium‐sensitive Cl− channels (CaCC), niflumic acid, had little effect on EAA release and only partially inhibited swelling‐activated Cl− currents. The phorbol ester PDBu, which blocks ClC‐3‐mediated Cl− currents, had no effect on VRAC currents and up‐regulated EAA release. In contrast, DCPIB, which selectively inhibits VRACs, potently suppressed both EAA release and VRAC currents. Two other relatively selective VRAC inhibitors, tamoxifen and phloretin, also blocked the VRAC currents and strongly reduced EAA release. Taken together, our data suggest that (i) astrocytic volume‐dependent EAA release is largely mediated by the VRAC, and (ii) the ClC‐2, ClC‐3, ClC‐4, ClC‐5, VDAC, CaCC, MDR‐1 and CFTR gene products do not contribute to EAA permeability.
Quality markers addressing preanalytical variations of blood and plasma processing identified by broad and targeted metabolite profiling.

BACKGROUND Metabolomics is a valuable tool with applications in almost all life science areas. There is an increasing awareness of the essential need for high-quality biospecimens in studies applying omics technologies and biomarker research. Tools to detect effects of both blood and plasma processing are a key for assuring reproducible and credible results. We report on the response of the human plasma metabolome to common preanalytical variations in a comprehensive metabolomics analysis to reveal such high-quality markers. METHODS Human EDTA blood was subjected to preanalytical variations while being processed to plasma: microclotting, prolonged processing times at different temperatures, hemolysis, and contamination with buffy layer. In a second experiment, EDTA plasma was incubated at different temperatures for up to 16 h. Samples were subjected to GC-MS and liquid chromatography-tandem mass spectrometry-based metabolite profiling (MxP™ Broad Profiling) complemented by targeted methods, i.e., sphingoids (as part of MxP™ Lipids), MxP™ Catecholamines, and MxP™ Eicosanoids. RESULTS Short-term storage of blood, hemolysis, and short-term storage of noncooled plasma resulted in statistically significant increases of 4% to 19% and decreases of 8% to 12% of the metabolites. Microclotting, contamination of plasma with buffy layer, and short-term storage of cooled plasma were of less impact on the metabolome (0% to 11% of metabolites increased, 0% to 8% decreased). CONCLUSIONS The response of the human plasma metabolome to preanalytical variation demands implementation of thorough quality assurance and QC measures to obtain reproducible and credible results from metabolomics studies. Metabolites identified as sensitive to preanalytics can be used to control for sample quality.