Miracle-dz/UniFAR-FTUs huggingface dataset:
Eravacycline Pharmacokinetics and Challenges in Defining Humanized Exposure In Vivo

ABSTRACT We assessed the pharmacokinetic profile of eravacycline, a novel antibiotic of the tetracycline class, and determined the dose in an immunocompetent murine thigh infection model that would provide free-drug exposure similar to that observed in humans after the administration of 1 mg/kg intravenously (i.v.) every 12 h (q12h). Eravacycline demonstrated a nonlinear protein-binding profile. The 2.5-mg/kg i.v. q12h dose in mice resulted in an area under the concentration-time curve for the free, unbound fraction of the drug of 1.64 mg · h/liter, which closely resembles the human exposure level.
Tirilazad Mesylate in Acute Ischemic Stroke: A Systematic Review

Background and Purpose Tirilazad is a nonglucocorticoid, 21-aminosteroid that inhibits lipid peroxidation. Studies in experimental models of ischemic stroke had suggested that tirilazad had neuroprotective properties. As a result, clinical studies were undertaken to assess the safety and efficacy of tirilazad in the treatment of acute ischemic stroke. We performed a systematic review of randomized, controlled trials that assessed the safety and efficacy of tirilazad in patients with acute ischemic stroke. Methods Trials of tirilazad were identified from searches of the Cochrane Library and communication with the Pharmacia & Upjohn company, the manufacturer of tirilazad. Data relating to early and end-of-trial case fatality, disability (Barthel Index and Glasgow Outcome Scale), phlebitis, and corrected QT interval were extracted by treatment group from published data and company reports and analyzed by using the Cochrane Collaboration meta-analysis software revman. Results Six trials (4 published, 2 unpublished) assessing tirilazad in 1757 patients with presumed acute ischemic stroke were identified; all were double-blind and placebo controlled in design. Tirilazad did not alter early case fatality (odds ratio [OR] 1.11, 95% confidence interval [CI] 0.79 to 1.56) or end-of-trial case fatality (OR 1.12, 95% CI 0.88 to 1.44). A just-significant increase in death and disability, assessed as either the expanded Barthel Index (OR 1.23, 95% CI 1.01 to 1.51) or Glasgow Outcome Scale (OR 1.23, 95% CI 1.01 to 1.50) was observed. Tirilazad significantly increased the rate of infusion site phlebitis (OR 2.81, 95% CI 2.14 to 3.69). Functional outcome (expanded Barthel Index) was significantly worse in prespecified subgroups of patients: females (OR 1.46, 95% CI 1.08 to 1.98) and subjects receiving low-dose tirilazad (OR 1.31, 95% CI 1.03 to 1.67); a nonsignificant worse outcome was also seen in patients with mild to moderate stroke (OR 1.40, 95% CI 0.99 to 1.98). Conclusions Tirilazad mesylate increases death and disability by about one fifth when given to patients with acute ischemic stroke. Although further trials of tirilazad are now unwarranted, analysis of individual patient data from the trials may help elucidate why tirilazad appears to worsen outcome in acute ischemic stroke.
Conditional Time Series Forecasting with Convolutional Neural Networks

textabstractForecasting financial time series using past observations has been a significant topic of interest. While temporal relationships in the data exist, they are difficult to analyze and predict accurately due to the non-linear trends and noise present in the series. We propose to learn these dependencies by a convolutional neural network. In particular the focus is on multivariate time series forecasting. Effectively, we use multiple financial time series as input in the neural network, thus conditioning the forecast of a time series x(t) on both its own history as well as that of a second (or third) time series y(t). Training a model on multiple stock series allows the network to exploit the correlation structure between these series so that the network can learn the market dynamics in shorter sequences of data. We show that long-term temporal dependencies in and between financial time series can be learned by means of a deep convolutional neural network based on the WaveNet model [2]. The network makes use of dilated convolutions applied to multiple time series so that the receptive field of the network is wide enough to learn both short and long-term dependencies. The architecture includes batch normalization and uses a 1 × k convolution with parametrized skip connections from the input time series as well as the time series we condition on, in this way learning long-term interdependencies in an efficient manner [1]. This improves the forecast, while at the same time limiting the requirement for a long historical price series and reducing the noise. Knowing the strong performance of CNNs on classification problems we show that they can be applied successfully to forecasting financial time series, without the need of large samples of data. We compare the performance of the WaveNet model to a state-of-the-art fully convolutional network (FCN), and an autoregressive model popular in econometrics and show that our model is much better able to learn important dependencies in between financial time series resulting in a more robust and accurate forecast.
La Volatilidad Implícita en las Opciones sobre Índices Bursátiles. Propuesta de Metodología de Estimación

A partir de 1987 se comprueba que la volatilidad que subyace en los precios de equilibrio en los mercados de opciones difiere de la volatilidad de los subyacentes y ademas, se rompe el supuesto de volatilidad constante e independiente del vencimiento. El calculo de la volatilidad implicita se realiza mediante optimizacion de la ecuacion de Black Scholes siendo dificil la deduccion de un algoritmo que la explique. Mediante Redes Neuronales se puede llegar a establecer un algoritmo sencillo que explica la volatilidad implicita en funcion del valor del subyacente del precio de ejercicio y del tiempo al vencimiento.
A Connectionist Approach to Making the Predictability of English Orthography Explicit to At-Risk Beginning Readers: Evidence for Alternative, Effective Strategies

A case is made (and illustrated with empirical data with children) for connectionist models that are not only computationally explicit but also instructionally explicit. First-graders (N = 128) at the bottom of their classes in reading (average 11.5 percentile on nationally normed tests) participated in a 3-layer intervention. In the first layer, kept constant for all treatment groups, the alphabet principle was taught, making functional spelling units and alternations explicit. In the second layer, which varied systematically across treatment groups, children received different kinds of tutor modeling in learning a set of words of varying spelling-sound predictability, using different connections between printed and spoken words, singly or in combination. In the third layer, also kept constant, children read and discussed illustrated books. Over the 4-month, 24-lesson intervention, all 7 treatment groups in the second layer improved more in word-specific learning than a contact control group that received phonological and orthographic awareness training without explicit instruction on orthographic-phonological connections. Of these 7, only 3 kinds of explicit modeling (whole word, letter-phoneme, and combined whole word and letter-phoneme) resulted in greater transfer to untrained words than the contact control or the other 4 kinds of explicit modeling. Results are discussed in reference to the controversy over whether dual route or connectionist models best account for the acquisition of reading.
Induction and regulation of IL-15 expression in murine macrophages.

IL-15 is a recently described cytokine which resembles IL-2 in its biologic activities, stimulating T cell and NK cell proliferation and activation as well as enhancing B cell expansion and Ab production. Unlike IL-2, IL-15 is not produced by lymphocytes, but instead (at least among cells of the immune system) appears to be synthesized primarily by monocyte/macrophages. We have examined the induction of IL-15 in murine macrophages (by semiquantitative reverse transcriptase-PCR and bioassay) in response to a variety of different macrophage-activating stimuli and compared the regulation of IL-15 production to that of IL-12 and TNF-alpha. Optimal induction of IL-15, in each of the macrophages populations tested, was found to require both priming (IFN-gamma) and triggering (LPS, mycobacteria, or Toxoplasma gondii) stimuli. When compared with IL-12 mRNA synthesis by the same macrophages, IL-15.mRNA production was more resistant to inhibition by the down-regulatory cytokines IL-14, IL-13, and TGF-beta. Moreover, IL-10, which is inhibitory for most other monokines, increased levels of IL-15 mRNA found after stimulation. These data establish IL-15 as a product of the macrophage/monocyte lineage, which is up-regulated on activation. IL-15 could thus play an important role in the initiation of immune responses by microbial agents.
Epidemiology and characteristics of adverse drug reactions caused by drug–drug interactions

Introduction: Drug–drug interactions (DDIs) arise in numerous different ways, involving pharmacokinetic or pharmacodynamic mechanisms. Adverse drug reactions are a possible consequence of DDIs and health operators are often unaware of the clinical risks of certain drug combinations. Many papers on drug interactions have been published in recent years, but most of them focused on potential DDIs while few studies have been conducted on actual interactions. Areas covered: This paper reviews the epidemiology of actual DDIs in outpatients as well as in hospital settings and in spontaneous reporting databases. The incidence of actual DDIs is consistently lower than that of potential DDIs. However, the absolute number of patients involved is high, representing a significant proportion of adverse drug reactions. The importance of risk factors such as age, polypharmacy and genetic polymorphisms is also evaluated. The relevance and efficacy of tools for recognizing and preventing DDIs are discussed. Expert opinion: Potential DDIs far outnumber actual drug interactions. The potential for an adverse interaction to occur is often theoretical, and clinically important adverse effects occur only in the presence of specific risk factors. Several studies have shown the efficacy of computers in early detection of DDIs. However, a correct risk–benefit evaluation by the prescribing physician, together with a careful clinical, physiological and biochemical monitoring of patients, is essential. Future directions of drug interaction research include the increasing importance of pharmacogenetics in preventing DDIs and the evaluation of interactions with biological drugs.
Beat the competition: a knowledge-based design process addressing the antenna effect and cell placement

Working within the application-specific integrated circuit (ASIC) industry, time to market is very important. With very deep submicron (VDSM) processes, issues with timing enclosure, cell placement efficiency, the antenna effect, signal integrity, etc., have impacted our ability to meet market requirements in a timely manner. By focusing on the design process, two of the major issues, the antenna problem and cell placement efficiency, can be addressed. I propose using knowledge-based priority placement (KBPP), which utilizes design knowledge to simplify those two issues.
Catheter Ablation of Ventricular Tachycardia in ARVC: Is Curative Treatment at the Horizon?

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized pathologically by fibro-fatty replacement of the right ventricular myocardium.1,2 Although segmental right ventricular disease is most commonly seen, evolution to a more diffuse right ventricular involvement and also left ventricular abnormalities has been described. Clinical manifestations include depolarization/repolarization abnormalities in the right precordial ECG leads, structural abnormalities of the right (and rarely left) ventricle, ventricular tachycardias (VT), and presentation with sudden cardiac death, and a family history of the disease. Criteria for diagnosis of ARVC include global and/or regional dysfunction, histologic tissue characteristics, repolarization and depolarization/conduction abnormalities, arrhythmias, and a family history.1,3 The typical clinical presentation of patients with ARVC contains the symptoms of ventricular arrhythmias, i.e., palpitations, syncope, or sudden cardiac death, with ventricular premature beats, nonsustained or sustained VT, or ventricular fibrillation (VF) as the underlying ventricular arrhythmias. An annual mortality rate of 2.3% was reported in a recently published retrospective analysis of 130 patients with ARVC.4 In that study, sudden cardiac death and heart failure represented the main components of overall mortality; and a history of VT, clinical signs of right ventricular failure, and left ventricular dysfunction were found to be predictors of long-term cardiovascular death.4 The main objective of arrhythmia management strategy in ARVC is to prevent recurrences of VT as well as to prevent sudden cardiac death. Implantable cardioverter-defibrillators (ICD), catheter ablation, and antiarrthythmic drugs are the cornerstone therapies available for patients with ARVC.
Influence of fitness on susceptibility to noise-induced temporary threshold shift.

PURPOSE Two earlier reports indicated that cardiovascular fitness attenuates susceptibility to noise-induced temporary threshold shift (TTS) in hearing sensitivity; however, other parameters of fitness also may be related to this phenomenon. This study investigated the association of three different physical fitness indicators on TTS. METHODS Maximal aerobic power (VO2max), body composition. and recent activity history were determined in 33 normal-hearing females of various fitness levels. Audiometric thresholds were obtained at 2000, 3000, 4000, and 6000 Hz before and immediately after 10 min of exposure to 108-dB SPL narrow-band noise centered at 2000 Hz. RESULTS All postnoise measurements were significantly less than prenoise measurements (P < 0.0001) with the greatest TTS occurring at 3000 Hz. Similarly, the strongest Pearson-product correlations for VO2max, % fat, and recent activity history with TTS occurred at 3000 Hz (r = -0.68, 0.60, -0.59, respectively; P < 0.05). Canonical correlation analysis indicated a moderate correlation between physical fitness and TTS (Rc = 0.71: P < 0.01). Individually, VO2max, % fat, and recent activity history had correlations of -0.70, 0.62, and -0.63, respectively, to the TTS canonical variable. CONCLUSIONS From these results, we concluded that there is a moderate association of physical fitness and diminished temporary hearing loss experienced after noise exposure.
Population pharmacokinetic/dynamic (PK/PD) modeling via the World Wide Web

A new research resource has been developed, allowing organizations with limited facilities for pharmacokinetic/pharmacodynamic (PK/PD) analysis to develop large and nonlinear nonparametric population models. The infrastructure described in this paper is flexible, reliable and secure. These resources are in use today by researchers in a number organizations and countries. Satellite installations continue to grow both nationally and internationally. The computational systems currently being made available through World Wide Web interfaces include the world's eighth largest supercomputer, smaller supercomputers and Beowulf systems. We first give a formulation of the problem. Then we give a description of infrastructure that is being used to overcome the problem. The last section contains an example of how the system is being used today.
The Obscure World of Integrative and Mobilizable Elements, Highly Widespread Elements that Pirate Bacterial Conjugative Systems

Conjugation is a key mechanism of bacterial evolution that involves mobile genetic elements. Recent findings indicated that the main actors of conjugative transfer are not the well-known conjugative or mobilizable plasmids but are the integrated elements. This paper reviews current knowledge on “integrative and mobilizable elements” (IMEs) that have recently been shown to be highly diverse and highly widespread but are still rarely described. IMEs encode their own excision and integration and use the conjugation machinery of unrelated co-resident conjugative element for their own transfer. Recent studies revealed a much more complex and much more diverse lifecycle than initially thought. Besides their main transmission as integrated elements, IMEs probably use plasmid-like strategies to ensure their maintenance after excision. Their interaction with conjugative elements reveals not only harmless hitchhikers but also hunters that use conjugative elements as target for their integration or harmful parasites that subvert the conjugative apparatus of incoming elements to invade cells that harbor them. IMEs carry genes conferring various functions, such as resistance to antibiotics, that can enhance the fitness of their hosts and that contribute to their maintenance in bacterial populations. Taken as a whole, IMEs are probably major contributors to bacterial evolution.
Preventing the collapse of the Baltic cod stock through an ecosystem-based management approach

Worldwide a number of fish stocks have collapsed because of overfishing and climate-induced ecosystem changes. Developing ecosystem-based fisheries management (EBFM) to prevent these catastrophic events in the future requires ecological models incorporating both internal food-web dynamics and external drivers such as fishing and climate. Using a stochastic food-web model for a large marine ecosystem (i.e., the Baltic Sea) hosting a commercially important cod stock, we were able to reconstruct the history of the stock. Moreover we demonstrate that in hindsight the collapse could only have been avoidable by adapting fishing pressure to environmental conditions and food-web interactions. The modeling approach presented here represents a significant advance for EBFM, the application of which is important for sustainable resource management in the future.
Plant Long ncRNAs: A New Frontier for Gene Regulatory Control

Long non-coding RNA (lncRNA) refers to an over 200 nt functional RNA molecule that will not be translated into protein. Previously thought to be dark matters of the genome, lncRNAs have been gradually recognized as crucial gene regulators. Although tremendous progress has been made in animals and human, the study of lncRNAs in plant is still in its infancy. Here, we reviewed the biogenesis and regulation mechanisms of lncRNAs and summarized the achievements that have been made in plant lncRNA identification and functional characterization. Genome-wide identification has uncovered large amount of lncRNAs in Arabidopsis, Rice, Maize and Wheat, and more information from other plant species will be expected with the aid of deep sequencing technologies. Similar to other species, LncRNA-mediated gene regulation also widely exists in plants, even though only a few functionally characterized examples are available. Up to now, at least four divergent lncRNA-mediated regulation mechanisms have been unraveled, including target mimicry, transcription interference, PRC2 associated histone methylation and DNA methylation. lncRNAs may be involved in the regulation of flowering, male sterility, nutrition metabolism, biotic and abiotic stress response in plants.
Tracheoesophageal Voice following Tubed Free Radial Forearm Flap Reconstruction of the Neopharynx

Tracheoesophageal voice restoration after laryngectomy is possible with a variety of neopharyngeal reconstructions. We have used the tubed radial forearm free flap for neopharyngeal reconstruction since 1991. Six patients have undergone voice restoration with the Blom-Singer prosthesis and were available for quantitative and qualitative speech analysis. These patients were compared to five laryngectomy patients with standard pharyngeal closures and similar voice restorations. The free flap patients produced similar loudness levels compared to the standards with soft speech (52.06 dB and 47.19 dB, respectively) and loud speech (62.66 dB and 60.91 dB, respectively). The free flap patients demonstrated adequate intelligibility, with fundamental frequencies comparable to standards (124.82 Hz and 135.66 Hz, respectively), although with increased jitter (5.00% versus 1.96%). No differences were statistically significant, but evaluation by trained and naive listeners demonstrated significant differences in voice quality. This quantitative and qualitative analysis of tracheoesophageal speech after radial forearm free flap reconstruction of the neopharynx demonstrates that acceptable voice can be achieved, but with limitations.
Social-contextual influences on expectancies for managing anger and sadness: the transition from middle childhood to adolescence.

This study examined the influence of emotion type (i.e., anger, sadness), audience type (i.e., mother, father, best friend), gender, and age on 140 5th-, 8th-, and 11th-grade adolescents' emotion management decisions, emotional self-efficacy, and outcome expectancies. Participants were read 8 vignettes and responded to 8 questions per vignette. Results indicated that 8th-grade adolescents reported regulating emotion most and expected the least interpersonal support from mothers. Children expressed greater self-efficacy and regulation of sadness than of anger. Boys reported dissembling emotion and expecting a negative interpersonal response to emotional behavior more than did girls. Children were more concerned with protecting feelings of friends than with protecting feelings of fathers.
Properties and Applications of Electrically Small Folded Ellipsoidal Helix Antenna

A comprehensive analysis of the radiation properties of an electrically small folded ellipsoidal helix antenna (EHA) is presented, showing its ability to self-resonate and impedance match without external components. Three antennas with different sizes and geometries have been designed to work at the 2.4-GHz ISM band and are realized using a selective laser sintering (SLS)-based fabrication process. The benefits of using this antenna for various size-restricted applications such as medical implants are also described.