Miracle-dz/UniFAR-FTUs huggingface dataset:
Frequency and Pattern of Heteroplasmy in the Complete Human Mitochondrial Genome

Determining the levels of human mitochondrial heteroplasmy is of utmost importance in several fields. In spite of this, there are currently few published works that have focused on this issue. In order to increase the knowledge of mitochondrial DNA (mtDNA) heteroplasmy, the main goal of this work is to investigate the frequency and the mutational spectrum of heteroplasmy in the human mtDNA genome. To address this, a set of nine primer pairs designed to avoid co-amplification of nuclear DNA (nDNA) sequences of mitochondrial origin (NUMTs) was used to amplify the mitochondrial genome in 101 individuals. The analysed individuals represent a collection with a balanced representation of genders and mtDNA haplogroup distribution, similar to that of a Western European population. The results show that the frequency of heteroplasmic individuals exceeds 61%. The frequency of point heteroplasmy is 28.7%, with a widespread distribution across the entire mtDNA. In addition, an excess of transitions in heteroplasmy were detected, suggesting that genetic drift and/or selection may be acting to reduce its frequency at population level. In fact, heteroplasmy at highly stable positions might have a greater impact on the viability of mitochondria, suggesting that purifying selection must be operating to prevent their fixation within individuals. This study analyses the frequency of heteroplasmy in a healthy population, carrying out an evolutionary analysis of the detected changes and providing a new perspective with important consequences in medical, evolutionary and forensic fields.
Network topology determines dynamics of the mammalian MAPK1,2 signaling network: bifan motif regulation of C‐Raf and B‐Raf isoforms by FGFR and MC1R

Activation of the fibroblast growth factor (FGFR) and melanocyte stimulating hormone (MC1R) receptors stimulates B‐Raf and C‐Raf isoforms that regulate the dynamics of MAPK1,2 signaling. Network topology motifs in mammalian cells include feed‐for ward and feedback loops and bifans where signals from two upstream molecules integrate to modulate the activity of two downstream molecules. We computation ally modeled and experimentally tested signal processing in the FGFR/MC1R/B‐Raf/C‐Raf/MAPK1,2 net work in human melanoma cells; identifying 7 regulatory loops and a bifan motif. Signaling from FGFR leads to sustained activation of MAPK1,2, whereas signaling from MC1R results in transient activation of MAPK1,2. The dynamics of MAPK activation depends critically on the expression level and connectivity to C‐Raf, which is critical for a sustained MAPK1,2 response. A partially incoherent bifan motif with a feedback loop acts as a logic gate to integrate signals and regulate duration of activation of the MAPK signaling cascade. Further reducing a 106‐node ordinary differential equations network encompassing the complete network to a 6‐node network encompassing rate‐limiting processes sustains the feedback loops and the bifan, providing sufficient information to predict biological responses. —Muller, M. , Obeyesekere, M. , Mills, G. B. , Ram, P. T. Network topology determines dynamics of the mammalian MAPK1,2 signaling network: bifan motif regulation of C‐Raf and B‐Raf isoforms by FGFR and MC1R. FASEB J. 22, 1393–1403 (2008)
The effects of temperature acclimation on the resting membrane of skeletal muscle fibres from green sunfish.

Conductive properties of muscle fibres from green sunfish (Lepomis cyanellus) acclimated to different temperatures were examined. The relative membrane permeability to chloride and potassium ions, PCl/PK, measured at acclimation temperature, was approximately 7.0 after acclimation at 25 degrees C and 1.3 after acclimation at 7 degrees C. This difference was due to a six-fold reduction in the membrane chloride conductance upon acclimation to 7 degrees C as compared to 25 degrees C-acclimated fibres. Mean (+/- S.E.M.) values of the chloride conductance were 554 +/- 68 microseconds cm-2 in warm-acclimated sunfish, and 75 +/- 9 microseconds cm-2 in cold-acclimated sunfish. Membrane capacitance also differed significantly between the two acclimation groups. When the temperature was varied acutely, the magnitude of the chloride conductance exhibited a maximum Q10 of only 1.9, compared with a Q10 of 3.0 associated with acclimation. Upon transferring 25 degrees C-acclimated sunfish to holding tanks at 7 degrees C, the total membrane resistance exhibited a sigmoidal increase over about 14 days, and a steady membrane capacitance was achieved in about 10 days. For 7 degrees C-acclimated sunfish, transferred to 25 degrees C, resistance showed a sigmoidal decrease over 10 days and capacitance was steady after 8 days. The results indicate that thermal acclimation of the muscle membrane involves cellular regulatory processes which underlie significant changes in the electrical properties of the fibre.
Supplier development or supplier switching?

We study a firm's cost-based sourcing decision of whether to invest in an incumbent supplier or switch to an alternative supplier in order to realise lower purchasing costs. In isolation, it can be shown that the development of an incumbent supplier (i.e., a cooperative investment) becomes more attractive, the higher the uncertainty about the price the buying firm can realise on the market and the incumbent supplier's cost. Likewise, switching to an alternative supplier becomes more attractive, the higher the expected value of and the uncertainty about the buying firm's market price. For comparing these two sourcing strategies simultaneously we provide a profit-maximising framework for the buying firm that shows that switching is less recommendable the higher the variance of the incumbent's cost and if the uncertain maximum demand is negatively correlated with the uncertain incumbent supplier's cost. Overall, our study substantially expands the frequently followed approach of basing supplier development versus supplier switching decisions merely on strategic and qualitative considerations.
Disentangling dynamic networks: Separated and joint expressions of functional connectivity patterns in time

Resting‐state functional connectivity (FC) is highly variable across the duration of a scan. Groups of coevolving connections, or reproducible patterns of dynamic FC (dFC), have been revealed in fluctuating FC by applying unsupervised learning techniques. Based on results from k‐means clustering and sliding‐window correlations, it has recently been hypothesized that dFC may cycle through several discrete FC states. Alternatively, it has been proposed to represent dFC as a linear combination of multiple FC patterns using principal component analysis. As it is unclear whether sparse or nonsparse combinations of FC patterns are most appropriate, and as this affects their interpretation and use as markers of cognitive processing, the goal of our study was to evaluate the impact of sparsity by performing an empirical evaluation of simulated, task‐based, and resting‐state dFC. To this aim, we applied matrix factorizations subject to variable constraints in the temporal domain and studied both the reproducibility of ensuing representations of dFC and the expression of FC patterns over time. During subject‐driven tasks, dFC was well described by alternating FC states in accordance with the nature of the data. The estimated FC patterns showed a rich structure with combinations of known functional networks enabling accurate identification of three different tasks. During rest, dFC was better described by multiple FC patterns that overlap. The executive control networks, which are critical for working memory, appeared grouped alternately with externally or internally oriented networks. These results suggest that combinations of FC patterns can provide a meaningful way to disentangle resting‐state dFC. Hum Brain Mapp 35:5984–5995, 2014. © 2014 The Authors. Human Brain Mapping published by Wiley Periodicals, Inc.
Industrial and Commercial Customer Response To Real Time Electricity Prices

Executive Summary This paper uses hourly data from industrial and commercial customers that volunteered to participate in Central and Southwest Service's (CSW) real-time pricing (RTP) programs to characterize the induced price response. The CSW RTP program, which adopted the two-part, revenue neutral design first introduced by Niagara Mohawk, was introduced to large commercial and industrial customers in Oklahoma 1994, and later in other jurisdictions. This study used summer months' price and usage data for the period 1998-2001. Most of the participants had gained substantial experience managing load under RTP by 1998, and this period was characterized by considerable price volatility. CSW allowed customers to choose from two RTP designs. Under the RTP program, a two-part, revenue neutral design, nearly identical to that introduced by Niagara Mohawk in 1988, participants received an hourly price schedule by 4:00 the day before it was effective. The RTP prices were used to settle variations in the following day's hourly energy usage from the customer's CBL. The CBL is an hour-by-hour representation of what the customer is deemed to have consumed on the standard CSW tariff otherwise applicable to the customer. Following established practice, CSW 2 established the CBL from each customer's historic usage. By construction, under this design participants are fully hedged against hourly RTP price variations at their typical load, but face prices that induce changes that result in economic efficiency improvements. Alternatively, customers could elect the RTP-LR option, whereby they nominated some of the CBL for additional, short-term hourly price exposure in return for a corresponding reduction in the tariff demand charge. For these participants, the day-ahead prices were provisional. CSW could, within specified limits, adjust their hourly prices upward by $38/kWh with only a single hour's notice, and simultaneously reduce their CBL by the amount of nominated load. Since these customers face greater price exposure, they were expected to be more price responsive. The price and quantity records of 54 participants were analyzed, of which 39 were enrolled in RTP for all three years, nine were in a program for two of the three years and six participated for a single year. A total of 43 customers enrolled in the RTP program, while 11 customers enrolled in a companion RTP-LR program. The study makes two important contributions to understanding of RTP participants' response to RTP prices. First, by adopting a demand model that allows price response to vary with the level …
cAMP-Dependent Protein Kinase Phosphorylations on Tau in Alzheimer’s Disease

To elucidate the role cAMP-dependent protein kinase (PKA) phosphorylations on tau play in Alzheimer’s disease, we have generated highly specific monoclonal antibodies, CP-3 and PG-5, which recognize the PKA-dependent phosphorylations of ser214 and ser409 in tau respectively. The present study demonstrates by immunohistochemical analysis, CP-3 and PG-5 immunoreactivity with neurofibrillary pathology in both early and advanced Alzheimer’s disease, but not in normal brain tissue and demonstrates that cAMP-dependent protein kinase phosphorylations on tau precede or are coincident with the initial appearance of filamentous aggregates of tau. Studies using heat-stable preparations demonstrate that neither site appears to be phosphorylated to any appreciable extent in normal rodent or human brain. Further analysis demonstrates that the β catalytic subunit of PKA (Cβ), the β II regulatory subunit of PKA (RIIβ), and the 79 kDa A-kinase-anchoring-protein (AKAP79), are tightly associated with the neurofibrillary pathology, positioning cAMP-dependent protein kinase to participate directly in the pathological hyperphosphorylation of tau seen in Alzheimer’s disease.
Structure and Asymptotic Theory for Multivariate Asymmetric Volatility: Empirical Evidence for Country Risk Ratings *

Following the rapid growth in the international debt of less developed countries in the 1970s and the increasing incidence of debt rescheduling in the early 1980s, country risk has become a topic of major concern for the international financial community. A critical assessment of country risk is essential because it reflects the ability and willingness of a country to service its financial obligations. Various risk rating agencies employ different methods to determine country risk ratings, combining a range of qualitative and quantitative information regarding alternative measures of economic, financial and political risk into associated composite risk ratings. This paper provides an international comparison of country risk ratings compiled by the International Country Risk Guide (ICRG), which is the only international rating agency to provide detailed and consistent monthly data over an extended period for a large number of countries. As risk ratings can be treated as indexes, their rate of change, or returns, merits attention in the same manner as financial returns. For this reason, a constant correlation multivariate asymmetric ARMA-GARCH model is presented and its underlying structure is established, including the unique, strictly stationary and ergodic solution of the model, its causal expansion, and convenient sufficient conditions for the existence of moments. Alternative empirically verifiable sufficient conditions for the consistency and asymptotic normality of the quasi-maximum likelihood estimator are established under non-normality of the conditional (or standardized) shocks. The empirical results provide a comparative assessment of the conditional means and volatilities associated with international country risk returns across countries and over time, enable a validation of the regularity conditions underlying the models, highlight the importance of economic, financial and political risk ratings as components of a composite risk rating, evaluate the multivariate effects of alternative risk returns and different countries, and evaluate the usefulness of the ICRG risk ratings in modelling risk returns.
The fantasy table

We explore the possibility of creating an interactive system which can foster fantasy play in preschool children in a tabletop environment. This paper reports our experiences designing and testing two prototypes with young children aged 3-4 years old. In the first study, we focused on understanding the similarities and differences between the type of play afforded by real objects and virtual objects. In the second study, we focused on testing solutions for the interaction difficulties evinced in the first study to see how to provide an engaging experience for children. Data were collected by observing children while they played with the study materials. Both quantitative and qualitative methods were used for data collection and analysis.
A strategy to replace the damaged element for fault-tolerant induction motor drive

In this paper, the best moment to replace to the damaged element in a fault-tolerant induction motor drive working with a open-loop and closed-loop control is presented, a previous stage of fault-diagnostic to detect a short-circuit or open-circuit failure in the power device is considered. The technique is based on the connection of bidirectional switches to electrically isolate the damaged element by mean of fuse blown corresponding and to replace only the damaged device by another healthful one at the most suitable moment, the main issue is to diminish the tracking error of the motor current during the fault transient. Experimental and simulation results are obtained in order to validate the technique proposed.
Incomplete Infection of Secondarily Infected Potato Plants – an Environment Dependent Underestimated Mechanism in Plant Virology

The common assumption in potato virus epidemiology is that all daughter tubers produced by plants coming from infected mother tubers (secondary infection) will become infected via systemic translocation of the virus during growth. We hypothesize that depending on the prevalent environmental conditions, only a portion of the daughter tubers of a plant that is secondarily infected by viruses may become infected. To test this hypothesis experimental data from standardized field experiments were produced in three contrasting environments at 112, 3280, and 4000 m a.s. l. in Peru during two growing seasons. In these experiments, the percentage of infected daughter tubers produced by seed tubers that were infected with either potato potexvirus X (PVX), potato Andean mottle comovirus (APMoV), potato potyvirus Y (PVY) (jointly infected with PVX) or potato leafroll luteovirus (PLRV) was determined. Incomplete autoinfection was found in all cases, as the percentage of virus infected daughter tubers harvested from secondarily infected plants was invariably less than 100%, with the lowest percentage of infection being 30%. Changing the growing site to higher altitudes decreased autoinfection for all viruses. Therefore, the assumption of complete autoinfection of secondarily infected plants were rejected, while the hypothesis of environmentally dependent incomplete autoinfection was accepted. The findings help explain the occurrence of traditional seed management practices in the Andes and may help to develop locally adapted seed systems in environments of the world that have no steady access to healthy seed tubers coming from a formally certified seed system. The results obtained almost three decades ago are discussed in light of most recent knowledge on epigenetic regulation of host plant – virus interactions which allow for speculating about the underlying biological principles of the incomplete autoinfection. A research roadmap is proposed for achieving explicit experimental proof for the epigenetic regulation of incomplete autoinfection in the pathosystem under study.
Software defect repair times: a multiplicative model

We analyzed over 10,000 software defect repair times collected for nine products at Cisco Systems, to confirm our hypothesis that software defect repair times can be characterized by the Laplace Transform of the Lognormal (LTLN) distribution. This hypothesis originated from the observation that software defect repair times are influenced by the multiplicative interplay of several factors. The Lognormal distribution is a natural choice to model rates of occurrence of such phenomenon. Conversion of the Lognormal rate distribution to an occurrence time distribution yields the LTLN. Our results also confirm that the LTLN distribution provides a statistically better fit to the observed repair times than either of the two most widely used repair time distributions, the lognormal and the exponential.
Measuring the effect of ubiquitous Internet success on travelers’ perceived value and overall tourism destination satisfaction

Abstract The Internet has not only gained wide-spread popularity; it has gradually become a necessity of modern life. In addition, the popularity of mobile devices has changed tourists’ travel habits; numerous travel activities can now be accessed through smartphone applications. As a result, Internet access has become a key requirement for tourism. Therefore, understanding the relationship between the availability of Internet access at a given tourist destination and the overall satisfaction of tourists at that destination is vital. This study modified the information systems (IS) success model to analyze how tourists’ perceived value of a tour and overall satisfaction is affected by the availability of Internet access. Questionnaires were distributed to 457 tourists who had made use of Macau’s ubiquitous Internet access. The IS success model was tested using structural equation modeling. The results revealed that Macau’s current level of Internet availability can positively influence value as perceived by tourists and enhance their satisfaction. The results of this study are expected to help Internet providers and related local tourism groups in Macau. Understanding the relationship between perceived value and overall satisfaction can greatly facilitate the use of these two factors, and could assist stakeholders in understanding that Macau’s Internet infrastructure must be improved for tourists.
A Case for Regulatory B Cells1

B cells are typically characterized by their ability to produce Abs, including autoantibodies. However, B cells possess additional immune functions, including the production of cytokines and the ability to function as a secondary APC. As with T cells, the B cell population contains functionally distinct subsets capable of performing both pathogenic and regulatory functions. Recent studies indicate that regulatory B cells develop in several murine models of chronic inflammation, including inflammatory bowel disease, rheumatoid arthritis, and experimental autoimmune encephalomyelitis. The regulatory function may be directly accomplished by the production of regulatory cytokines IL-10 and TGF-β and/or by the ability of B cells to interact with pathogenic T cells to dampen harmful immune responses. In this review, we make a case for the existence of regulatory B cells and discuss the possible developmental pathways and functional mechanisms of these B cells.
Precision timing measurements of PSR J1012+5307

We present results and applications of high-precision timing measurements of the binary millisecond pulsar J1012+5307. Combining our radio timing measurements with results based on optical observations, we derive complete 3D velocity information for this system. Correcting for Doppler effects, we derive the intrinsic spin parameters of this pulsar and a characteristic age of 8.6±1.9 Gyr. Our upper limit for the orbital eccentricity of only 8×10−7 (68 per cent confidence level) is the smallest ever measured for a binary system. We demonstrate that this makes the pulsar an ideal laboratory in which to test certain aspects of alternative theories of gravitation. Our precision measurements suggest deviations from a simple pulsar spin-down timing model, which are consistent with timing noise and the extrapolation of the known behaviour of slowly rotating pulsars.
On the conditioning of finite element equations with highly refined meshes

It is proven that the condition number of the linear system representing a finite element discretization of an elliptic boundary value problem does not degrade significantly as the mesh is refined locally, provided the mesh remains nondegenerate and a natural scaling of the basis functions is used. Bounds for the Euclidean condition number as a function of the number of degrees f freedom are derived in $n \geq 2$ dimensions. When $n \geq 3$ the bound is the same as for the regular mesh case, but when $n = 2$ a factor appears in the bound for the condition number that is logarithmic in the ratio of the maximum and minimum mesh sizes. Applications of the results to the conjugate-gradient iterative method for solving such linear systems are given.
Calcitriol Inhibits Hedgehog Signaling and Induces Vitamin D Receptor Signaling and Differentiation in the Patched Mouse Model of Embryonal Rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Aberrant Hedgehog (Hh) signaling is characteristic of the embryonal subtype (ERMS) and of fusion-negative alveolar RMS. In the mouse, ERMS-like tumors can be induced by mutations in the Hh receptor Patched1 (Ptch). As in humans these tumors show increased Hh pathway activity. Here we demonstrate that the treatment with the active form of vitamin D3, calcitriol, inhibits Hh signaling and proliferation of murine ERMS in vivo and in vitro. Concomitantly, calcitriol activates vitamin D receptor (Vdr) signaling and induces tumor differentiation. In addition, calcitriol inhibits ERMS growth in Ptch-mutant mice, which is, however, a rather late response. Taken together, our results suggest that exogenous supply of calcitriol could be beneficial in the treatment of RMS, especially in those which are associated with aberrant Hh signaling activity.