Miracle-dz/UniFAR-FTUs huggingface dataset:
An Alternative Pathway for Okazaki Fragment Processing

Two pathways have been proposed for eukaryotic Okazaki fragment RNA primer removal. Results presented here provide evidence for an alternative pathway. Primer extension by DNA polymerase δ (pol δ) displaces the downstream fragment into an RNA-initiated flap. Most flaps are cleaved by flap endonuclease 1 (FEN1) while short, and the remaining nicks joined in the first pathway. A small fraction escapes immediate FEN1 cleavage and is further lengthened by Pif1 helicase. Long flaps are bound by replication protein A (RPA), which inhibits FEN1. In the second pathway, Dna2 nuclease cleaves an RPA-bound flap and displaces RPA, leaving a short flap for FEN1. Pif1 flap lengthening creates a requirement for Dna2. This relationship should not have evolved unless Pif1 had an important role in fragment processing. In this study, biochemical reconstitution experiments were used to gain insight into this role. Pif1 did not promote synthesis through GC-rich sequences, which impede strand displacement. Pif1 was also unable to open fold-back flaps that are immune to cleavage by either FEN1 or Dna2 and cannot be bound by RPA. However, Pif1 working with pol δ readily unwound a full-length Okazaki fragment initiated by a fold-back flap. Additionally, a fold-back in the template slowed pol δ synthesis, so that the fragment could be removed before ligation to the lagging strand. These results suggest an alternative pathway in which Pif1 removes Okazaki fragments initiated by fold-back flaps in vivo.
Commentary(McDermott/Hudes)—Testicular Cancer: Maintaining the High Cure Rate

Dr. Raghavan is to be commended for a concise and comprehensive overview of the management of germ cell tumors. As he suggests, given the demographics of this relatively uncommon disease and the high cure rate that can be achieved with proper treatment and follow-up, it behooves us to maintain these excellent results, even while striving to reduce the toxicity of treatment. We will highlight a few additional points to complement this superb review.
Data‐based theoretical identification of subcellular calcium compartments and estimation of calcium dynamics in cardiac myocytes

• Ca2+ release from intracellular stores affects the cardiac action potential via currents through L‐type Ca2+ channels (ICa) and the sodium/calcium exchanger (INCX). • Dynamic interactions between released calcium, ICa and INCX occur in a restricted subcellular compartment, close to Ca2+ released sites, where calcium concentration (Cat) cannot be measured. • We used a computational model and experimental data to define this compartment and to provide a theoretical basis for estimating Cat. • We estimated Cat from recordings of ICa and INCX and optical recordings of whole‐cell calcium concentration (Cam). • Estimated peak Cat ranged from 6 μm to 25 μm, depending on calcium load. Time to equilibrium between Cat and Cam was ∼350 ms. The Cat values are in the range of ICa and INCX sensitivity to calcium, implying that there is significant effect of Ca2+ in this restricted domain on their kinetics and on the action potential during cell excitation.
Mechanisms of Barbiturate Inhibition of Acetylcholine Receptor Channels

We used patch clamp techniques to study the inhibitory effects of pentobarbital and barbital on nicotinic acetylcholine receptor channels from BC3H-1 cells. Single channel recording from outside-out patches reveals that both drugs cause acetylcholine-activated channel events to occur in bursts. The mean duration of gaps within bursts is 2 ms for 0.1 mM pentobarbital and 0.05 ms for 1 mM barbital. In addition, 1 mM barbital reduces the apparent single channel current by 15%. Both barbiturates decrease the duration of openings within a burst but have only a small effect on the burst duration. Macroscopic currents were activated by rapid perfusion of 300 μM acetylcholine to outside-out patches. The concentration dependence of peak current inhibition was fit with a Hill function; for pentobarbital, K i = 32 μM, n = 1.09; for barbital, K i = 1900 μM, n = 1.24. Inhibition is voltage independent. The kinetics of inhibition by pentobarbital are at least 30 times faster than inhibition by barbital (3 ms vs. <0.1 ms at the K i). Pentobarbital binds ≥10-fold more tightly to open channels than to closed channels; we could not determine whether the binding of barbital is state dependent. Experiments performed with both barbiturates reveal that they do not compete for a single binding site on the acetylcholine receptor channel protein, but the binding of one barbiturate destabilizes the binding of the other. These results support a kinetic model in which barbiturates bind to both open and closed states of the AChR and block the flow of ions through the channel. An additional, lower-affinity binding site for pentobarbital may explain the effects seen at >100 μM pentobarbital.
Construct Validity and Factor Structure of the Pittsburgh Sleep Quality Index and Epworth Sleepiness Scale in a Multi-National Study of African, South East Asian and South American College Students

Background The Pittsburgh Sleep Quality Index (PSQI) and the Epworth Sleepiness Scale (ESS) are questionnaires used to assess sleep quality and excessive daytime sleepiness in clinical and population-based studies. The present study aimed to evaluate the construct validity and factor structure of the PSQI and ESS questionnaires among young adults in four countries (Chile, Ethiopia, Peru and Thailand). Methods A cross-sectional study was conducted among 8,481 undergraduate students. Students were invited to complete a self-administered questionnaire that collected information about lifestyle, demographic, and sleep characteristics. In each country, the construct validity and factorial structures of PSQI and ESS questionnaires were tested through exploratory and confirmatory factor analyses (EFA and CFA). Results The largest component-total correlation coefficient for sleep quality as assessed using PSQI was noted in Chile (r = 0.71) while the smallest component-total correlation coefficient was noted for sleep medication use in Peru (r = 0.28). The largest component-total correlation coefficient for excessive daytime sleepiness as assessed using ESS was found for item 1 (sitting/reading) in Chile (r = 0.65) while the lowest item-total correlation was observed for item 6 (sitting and talking to someone) in Thailand (r = 0.35). Using both EFA and CFA a two-factor model was found for PSQI questionnaire in Chile, Ethiopia and Thailand while a three-factor model was found for Peru. For the ESS questionnaire, we noted two factors for all four countries Conclusion Overall, we documented cross-cultural comparability of sleep quality and excessive daytime sleepiness measures using the PSQI and ESS questionnaires among Asian, South American and African young adults. Although both the PSQI and ESS were originally developed as single-factor questionnaires, the results of our EFA and CFA revealed the multi- dimensionality of the scales suggesting limited usefulness of the global PSQI and ESS scores to assess sleep quality and excessive daytime sleepiness.
SPEAKER LOCALIZATION EXPLOITING SPATIAL-TEMPORAL INFORMATION

Determining the spatial position of a speaker finds a growing interest in video conference scenario where automated camera steering and tracking are required. Speaker localization can be achieved with a dual step approach. In the preliminary stage microphone array is used to extract the time difference of arrival (TDOA) of the speech signal. These readings are then used by the second stage for the actual localization. Since speaker trajectory must be smooth, estimates of close speaker positions might be used to improve the current position estimate. However, many methods, although exploiting the spatial information obtained by dierent microphone pairs, do not exploit this temporal information. In this contribution we present two localization schemes, which exploit the temporal information. The first is the well known extended Kalman filter (EKF). The second is a recursive form of a Gauss method, which we denote Recursive Gauss (RG). Experimental study supports the potential of the proposed methods.
Tactual Illusions

16 college males participated in a study exploring active and passive illusions in touch. Analogs to 2 primary and 2 secondary visual illusions were constructed for active and for passive tactual presentation. Tactual illusory effects similar to those one would predict from vision were found in the active mode of presentation of the Müller-Lyer, and horizontal-vertical conditions, while opposite effects were found in the active mode of presentation of a modification of Delboeuf circles and in the passive diamond-square and horizontal-vertical conditions (ps < .02). Analogous primary and secondary illusory results interacted with the active and passive modes of presentation.
Long-Term Use of Contraceptive Depot Medroxyprogesterone Acetate in Young Women Impairs Arterial Endothelial Function Assessed by Cardiovascular Magnetic Resonance

Background—Depot medroxyprogesterone acetate (DMPA) inhibits proliferation of ovarian follicles, resulting in anovulation and a decrease in circulating estrogen; the latter action is potentially disadvantageous to cardiovascular health. We therefore investigated the vascular effects of long-term contraceptive DMPA in young women. Methods and Results—Endothelium-dependent (hyperemia-induced flow-mediated dilatation [FMD]) and -independent (glyceryl trinitrate [GTN]) changes in brachial artery area were measured using cardiovascular magnetic resonance in 13 amenorrheic DMPA users (>1 year use; mean age 29±4 years) and in 10 controls (mean age 30±4 years, P =0.25) with regular menstrual cycles after validation of the technique. FMD and GTN responses were measured just before repeat MPA injection and 48 hours later (n=12) in DMPA users and during menstruation and midcycle (n=9) in controls. Serum-estradiol levels (S-estradiol) were measured at both visits. FMD was reduced in DMPA users compared with controls during menstruation (1.1% versus 8.0%, respectively P <0.01) without differences in GTN responses. S-estradiol levels in DMPA users were significantly lower than in controls during menstruation (58 versus 96 pmol/L, P <0.01). High levels of circulating MPA 48 hours after injection were not linked to an additional impairment in FMD (2.0% versus 3.1%, P =0.23). Estradiol levels were significantly correlated to FMD (r =0.43, P <0.01). Conclusions—Endothelium-dependent arterial function measured by cardiovascular magnetic resonance is impaired in chronic users of DMPA, and hypoestrogenism may be the mechanism of action. DMPA might adversely affect cardiovascular health, and in particular its use in women with cardiovascular disease should be additionally evaluated.
Beat Frequency Detector--Based High-Speed True Random Number Generators: Statistical Modeling and Analysis

True random number generators (TRNGs) are crucial components for the security of cryptographic systems. In contrast to pseudo--random number generators (PRNGs), TRNGs provide higher security by extracting randomness from physical phenomena. To evaluate a TRNG, statistical properties of the circuit model and raw bitstream should be studied. In this article, a model for the beat frequency detector--based high-speed TRNG (BFD-TRNG) is proposed. The parameters of the model are extracted from the experimental data of a test chip. A statistical analysis of the proposed model is carried out to derive mean and variance of the counter values of the TRNG. Our statistical analysis results show that mean of the counter values is inversely proportional to the frequency difference of the two ring oscillators (ROSCs), whereas the dynamic range of the counter values increases linearly with standard deviation of environmental noise and decreases with increase of the frequency difference. Without the measurements from the test data, a model cannot be created; similarly, without a model, performance of a TRNG cannot be predicted. The key contribution of the proposed approach lies in fitting the model to measured data and the ability to use the model to predict performance of BFD-TRNGs that have not been fabricated. Several novel alternate BFD-TRNG architectures are also proposed; these include parallel BFD, cascade BFD, and parallel-cascade BFD. These TRNGs are analyzed using the proposed model, and it is shown that the parallel BFD structure requires less area per bit, whereas the cascade BFD structure has a larger dynamic range while maintaining the same mean of the counter values as the original BFD-TRNG. It is shown that 3.25M and 4M random bits can be obtained per counter value from parallel BFD and parallel-cascade BFD, respectively, where M counter values are computed in parallel. Furthermore, the statistical analysis results illustrate that BFD-TRNGs have better randomness and less cost per bit than other existing ROSC-TRNG designs. For example, it is shown that BFD-TRNGs accumulate 150% more jitter than the original two-oscillator TRNG and that parallel BFD-TRNGs require one-third power and one-half area for same number of random bits for a specified period.
Net Clinical Benefit of Oral Anticoagulants: A Multiple Criteria Decision Analysis

Background This study quantitatively evaluated the comparative efficacy and safety of new oral anticoagulants (dabigatran, rivaroxaban, and apizaban) and warfarin for treatment of nonvalvular atrial fibrillation. We also compared these agents under different scenarios, including population with high risk of stroke and for primary vs. secondary stroke prevention. Methods We used multiple criteria decision analysis (MCDA) to assess the benefit-risk of these medications. Our MCDA models contained criteria for benefits (prevention of ischemic stroke and systemic embolism) and risks (intracranial and extracranial bleeding). We calculated a performance score for each drug accounting for benefits and risks in comparison to treatment alternatives. Results Overall, new agents had higher performance scores than warfarin; in order of performance scores: dabigatran 150 mg (0.529), rivaroxaban (0.462), apixaban (0.426), and warfarin (0.191). For patients at a higher risk of stroke (CHADS2 score≥3), apixaban had the highest performance score (0.686); performance scores for other drugs were 0.462 for dabigatran 150 mg, 0.392 for dabigatran 110 mg, 0.271 for rivaroxaban, and 0.116 for warfarin. Dabigatran 150 mg had the highest performance score for primary stroke prevention, while dabigatran 110 mg had the highest performance score for secondary prevention. Conclusions Our results suggest that new oral anticoagulants might be preferred over warfarin. Selecting appropriate medicines according to the patient’s condition based on information from an integrated benefit-risk assessment of treatment options is crucial to achieve optimal clinical outcomes.
PAIRWISE VERSUS DIFFUSE NATURAL SELECTION AND THE MULTIPLE HERBIVORES OF SCARLET GILIA, IPOMOPSIS AGGREGATA

Recent theoretical studies have argued that plant‐herbivore coevolution proceeds in a diffuse rather than a pairwise manner in multispecies interactions when at least one of two conditions are met: (1) genetic correlations exist between plant resistances to different herbivore species; and (2) ecological interactions between herbivores sharing a host plant cause nonadditive impacts of herbivory on plant fitness. We present results from manipulative field experiments investigating the single and interactive fitness effects of three types of herbivory on scarlet gilia (Ipomopsis aggregata) over two years of study. We utilize these data to test whether selection imposed by herbivore attack on date of first flowering is pairwise (independent) or diffuse (dependent) in nature. Our results reveal complex patterns of the fitness effect of herbivores. Simulated early season browsing had a strong negative fitness effect on plants and also reduced subsequent insect attack. Surprisingly, this ecological interaction did not translate into significant interactions between clipping and insect manipulations on plant fitness. However, we detected a significant interaction between seed fly and caterpillar herbivory on plant fitness, with the negative effect of either insect being greatest when occurring alone. These results suggest that herbivore‐imposed selection may have pairwise and diffuse components. In our selection analysis of flowering phenology, we discovered significant pairwise linear selection imposed by clipping, diffuse linear selection imposed by insects, and diffuse nonlinear selection imposed by clipping and insect attack acting simultaneously. Our results reveal that the evolution of flowering phenology in scarlet gilia may be in response to diffuse and pairwise natural selection imposed by multiple herbivores. We discuss the evolution of resistance characters in light of diffuse versus pairwise forms of linear and nonlinear selection and stress the complexity of selection imposed by suites of interacting species.
Network Positions and Contributions to Online Public Goods: The Case of Chinese Wikipedia

We study the effect of collaboration network structure on the contribution behavior of participating editors in Wikipedia. Collaboration in Wikipedia is organized around articles, and any two editors co-editing an article have a collaborative relationship. Based on the economic theories about network games and social role theory, we propose that an editor's position in the collaboration network influences the editor's decisions about her total contribution as well as the allocation of her efforts. By leveraging panel data collected from the Chinese language version of Wikipedia and a natural experiment resulting from blocking it in mainland China, we find strong support for the proposed effect of network position on contribution behavior. Our analysis further reveals that different aspects of an individual's network position have distinct implications. This research enhances our understanding about how collaboration network structure shapes individual behavior in online mass collaboration platforms.
Separation of the Systems for Color and Spatial Manipulation in Working Memory Revealed by a Dual-task Procedure

The manipulation of different kinds of content is fundamental to working memory. It has been suggested that the mere maintenance of color and spatial information occurs in parallel, but little is known about whether this holds true for manipulation as well. Using a dual-task delayed-response paradigm that required the manipulation of color and angles, this study finds that the two functions do not interfere. Conversely, interference did occur when both components of a dual-task tapped into the spatial system. Thus, color and spatial information are manipulated in parallel. A concurrent phonological task did not interfere with either maintenance or manipulation, whereas a task requiring central executive processes interfered with manipulation only. We speculate that the ventraldorsal dissociation of visual processing is conserved for manipulation processes and that manipulation differs from maintenance in the extent to which is relies on central executive resources.
Utility analysis of parallel simulation

Parallel computers are used to execute discrete event simulations in contexts where a serial computer is unable to provide answers fast enough, and/or is unable to hold the simulation state in memory. Traditional research in parallel simulation has focused on the degree to which a parallel simulator provides speedup. We take a different view and ask how a parallel simulator provides increased user defined utility as a result of being able to simulate larger problem sizes. We develop a model where the utility of simulating a particular simulation is an increasing function of the problem size, and ask whether overall utility accrues faster on a parallel computer if one uses it to simulate one large problem in parallel, several smaller problem instances concurrently and each in parallel, or concurrently many small problem instances on single processors. We show that under our model assumptions, utility is accrued faster either by running one large problem instance in parallel using all the available processors, or by running one small problem instance per processor, concurrently. When we consider how to optimize the utility per unit cost we find that one either runs a large problem using all available processors, multiple small problems with one per processor, or a small problem using exactly one processor. Determination of the optimal configuration depends on the user's assessment of how rapidly utility grows with the problem size. Our main contribution is to show the linkage between the effectiveness of parallel simulation and a user's perception of the value of larger problem sizes. We show that if that utility grows less than linearly in the problem size, then use of parallelism is sub-optimal. We give precise relationships between our model parameters that govern when parallelism optimizes utility, and when it optimizes price-performance. We see that when model parameters are in a "normal" range, a user's perception of utility must grow significantly-e.g. proportional to problem size raised to the 1.5th power-for parallel processing to optimize cost performance.
Fast and Provably Good Seedings for k-Means

Seeding - the task of finding initial cluster centers - is critical in obtaining high-quality clusterings for k-Means. However, k-means++ seeding, the state of the art algorithm, does not scale well to massive datasets as it is inherently sequential and requires k full passes through the data. It was recently shown that Markov chain Monte Carlo sampling can be used to efficiently approximate the seeding step of k-means++. However, this result requires assumptions on the data generating distribution. We propose a simple yet fast seeding algorithm that produces *provably* good clusterings even *without assumptions* on the data. Our analysis shows that the algorithm allows for a favourable trade-off between solution quality and computational cost, speeding up k-means++ seeding by up to several orders of magnitude. We validate our theoretical results in extensive experiments on a variety of real-world data sets.
Evidence of a genetic factor in migraine with aura: A population‐based Danish twin study

We studied the genetic influence on cause of migraine with aura (MA) by analyzing a twin population. The twin sample consisted of 2,026 monozygotic (MZ) twins and 3,334 same‐sex dizygotic (DZ) twins, born from 1953 to 1960, from the population‐based New Danish Twin Register. A validated questionnaire was used to screen for migraine, the response rate being 87%, and similar among MZ and DZ twins. All twin pairs with at least 1 twin with possible MA were interviewed by a physician experienced in headache diagnoses. The answers from the questionnaire as well as the zygosity of the twins were blinded for the interviewer. A total of 211 twin pairs were identified, of whom 77 pairs were MZ and 134 pairs were DZ. The lifetime prevalence of MA was 7% and with a male‐to‐female ratio of 1:1.1. The pairwise concordance rates were significantly higher in MZ (34%) than in DZ twin pairs (12%), emphasizing the importance of genetic factors in MA. However, environmental factors are also important, as the pairwise concordance rate was less than 100% in MZ twin pairs. The recurrence risk of MA was 50% in MZ and 21% in DZ twin pairs. In nontwin siblings, the recurrence risk of MA is 27%, which is similar to the recurrence risk in DZ twins. This indicates that MA is not developed due to specific environmental factors shared by the twins. Ann Neurol 1999;45:242–246