Prognostic implications of the ID1 expression in acute myeloid leukemia patients treated in a resource-constrained setting.

INTRODUCTION: The aberrant expression of the inhibitor of DNA binding (ID1) gene has been frequently associated with the leukemogenesis and prognostication acute myeloid leukemia (AML), although its clinical importance has never been investigated in patients treated outside well-controlled clinical trials. METHODS: Using quantitative real-time polymerase chain reaction, we investigated the role of the ID1 expression in the clinical outcomes of non-selected patients with acute myeloid leukemia treated in a real-life setting. RESULTS: Overall, 128 patients were enrolled. Patients with high ID1 expression had a lower 3-year overall survival (OS) rate of 9%, with the 95% confidence interval (95%CI) at 3 to 20%, compared to patients with a low ID1 expression (22%, 95%CI: 11 - 34%) (p = 0.037), although these findings did not retain significance after adjustment (hazard ratio (HR): 1.5, 95%CI: 0.98 - 2.28; p = 0.057). The ID1 expression had no impact on post-induction outcomes (disease-free survival, p = 0.648; cumulative incidence of relapse, p = 0.584). CONCLUSIONS: Although we are aware thar our data are confronted with many variables that cannot be fully controlled, including drug unavailability, risk-adapted treatment, comorbidities and the time from diagnosis to treatment initiation, we are firm believers that such an initiative can provide more realistic data on understudied populations, in particular those from low- and middle-income countries.

Clinical significance of mitochondrial DNA content in acute promyelocytic leukaemia.

Although a growing body of evidence demonstrates that altered mtDNA content (mtDNAc) has clinical implications in several types of solid tumours, its prognostic relevance in acute promyelocytic leukaemia (APL) patients remains largely unknown. Here, we show that patients with higher-than-normal mtDNAc had better outcomes regardless of tumour burden. These results were more evident in patients with low-risk of relapse. The multivariate Cox proportional hazard model demonstrated that high mtDNAc was independently associated with a decreased cumulative incidence of relapse. Altogether, our data highlights the possible role of mitochondrial metabolism in APL patients treated with ATRA.

Providing organic macro minerals and an elevated platform improved tibia characteristics, and increased locomotion and performance of fast- and slower-growing broilers.

Improving leg health will support broiler health and welfare. Known factors to improve leg health are: replacing inorganic by organic macro minerals in the diet, providing environmental enrichments and using slower-growing broilers. However, it remains unknown how fast- and slower-growing broilers respond to a combination of providing organic macro minerals and an elevated platform as enrichment with regard to leg health. Therefore, the aim of this study was to identify whether a combined treatment of organic macro minerals and a platform affected leg health, tibia characteristics, behavior and performance of fast- and slower-growing broilers in a semicommercial setting. The experiment had a 2 × 2 factorial arrangement, with 12.800 fast-growing (Ross 308) and 12.800 slower-growing (Hubbard JA757) broilers that were randomly allocated to a control (i.e., inorganic macro minerals without enrichment) or adapted treatment (i.e., organic macro minerals and a platform). Broilers were housed in groups of 800 per pen (47.5 m2), with 8 replicates per treatment (total of 32 pens). Performance was measured weekly and over the total rearing period. Behavior was observed via scan sampling at a target weight of 0.6 and 1.9 kg for both breeds. Walking ability (gait score), footpad dermatitis, and hock burn were assessed in 10 broilers per pen just prior to slaughter weight. Leg disorders and tibia characteristics were assessed in the same broilers at slaughter weight (2.3 kg). Hardly any interaction effects between breed and treatment were found on leg health, tibia characteristics, behavior or performance, suggesting fast- and slower-growing broilers responded to the treatment similarly. The adapted treatment improved tibia characteristics, and increased locomotion and performance, but did not affect leg disorders, walking ability or contact dermatitis in both fast- and slower-growing broilers. The positive effects of the adapted treatment on tibia characteristics in both fast- and slower-growing broilers may improve leg health, although the current study did not confirm this for leg disorders, walking ability or contact dermatitis.

The impact of dietary calcium content on phosphorus absorption and retention in growing pigs is enhanced by dietary microbial phytase supplementation.

Sixty growing male pigs were used to test the hypothesis that high dietary Ca content reduces P absorption to a greater extent in microbial phytase-supplemented diets via reducing inositol phosphate (IP) degradation and enhancing P precipitation. Pigs were equally allotted over diets with three Ca contents 2·0, 5·8 and 9·6 g/kg with or without microbial phytase (0 v. 500 FTU/kg) in a 2 × 3 factorial arrangement. Faeces and urine were collected at the end of the 21-d experimental period. Subsequently, pigs were euthanised and digesta quantitatively collected from different gastrointestinal tract (GIT) segments. Increasing dietary Ca content reduced apparent P digestibility in all GIT segments posterior to the stomach (P < 0·001), with greater effect in phytase-supplemented diets in the distal small intestine (Pinteraction = 0·007) and total tract (Pinteraction = 0·023). Nonetheless, increasing dietary Ca to 5·8 g/kg enhanced P retention, but only in phytase-supplemented diets. Ileal IP6 degradation increased with phytase (P < 0·001) but decreased with increasing dietary Ca content (P = 0·014). Proportion of IP esters in total IP (∑IP) indicated that IP6/∑IP was increased while IP4/∑IP and IP3/∑IP were reduced with increasing dietary Ca content and also with a greater impact in phytase-supplemented diets (Pinteraction = 0·025, 0·018 and 0·009, respectively). In all GIT segments, P solubility was increased with phytase (P < 0·001) and tended to be reduced with dietary Ca content (P < 0·096). Measurements in GIT segments showed that increasing dietary Ca content reduced apparent P digestibility via reducing IP degradation and enhancing P precipitation, with a greater impact in phytase-supplemented diets due to reduced IP degradation.

Regulating appetite in broilers for improving body and muscle development - A review.

Appetite is the desire for feed and water and the voluntary intake of feed and is an important regulator of livestock productivity and animal health. Economic traits such as growth rate and muscle development (meat deposition) in broilers are directly correlated to appetite. Factors that may influence appetite include environmental factors, such as stress and temperature variation, and animal-specific factors, such as learning period, eating capacity and preferences. Feed preferences have been reported to be determined in early life, and this period is important in broilers due to their fast growth and relatively short growth trajectories. This may be of importance when contemplating the use of more circular and sustainable feeds and the optimization of appetite for these feeds. The objective of this review was to review the biological mechanisms underlying appetite using data from human, animal and bird models and to consider the option for modulating appetite particularly as it relates to broiler chickens.

Touchscreens for Aircraft Navigation Tasks: Comparing Accuracy and Throughput of Three Flight Deck Interfaces Using Fitts' Law.

OBJECTIVE: Use Fitts' law to compare accuracy and throughput of three flight deck interfaces for navigation. BACKGROUND: Industry is proposing touch-based solutions to modernize the flight management system. However, research evaluating touchscreen effectiveness for navigation tasks in terms of accuracy and throughput on the flight deck is lacking. METHOD: An experiment was conducted with 14 participants in a flight simulator, aimed at creating Fitts' law accuracy and throughput models of three different flight deck interfaces used for navigation: the mode control panel, control display unit, and a touch-based navigation display. The former two constitute the conventional interface between the pilot and the flight management system, and the latter represents the industry-proposed solution for the future. RESULTS: Results indicate less accurate performance with the touchscreen navigation display compared to the other two interfaces and the throughput was lowest with the mode control panel. The control display unit was better in both accuracy and throughput, which is found to be largely attributed to the tactile and physical nature of the interface. CONCLUSION: Although performance in terms of accuracy and throughput was better with the control display unit, a question remains whether, when used during a more realistic navigation task, performance is still better compared to a touch-based interface. APPLICATION: This paper complements previous studies in the usage of aircraft touchscreens with new empirical insights into their accuracy and throughput, compared to conventional flight deck interfaces, using Fitts' law.

Effects of Target Signal Shape and System Dynamics on Feedforward in Manual Control.

The human controller (HC) in manual control of a dynamical system often follows a visible and predictable reference path (target). The HC can adopt a control strategy combining closed-loop feedback and an open-loop feedforward response. The effects of the target signal waveform shape and the system dynamics on the human feedforward dynamics are still largely unknown, even for common, stable, vehicle-like dynamics. This paper studies the feedforward dynamics through computer model simulations and compares these to system identification results from human-in-the-loop experimental data. Two target waveform shapes are considered, constant velocity ramp segments and constant acceleration parabola segments. Furthermore, three representative vehicle-like system dynamics are considered: 1) a single integrator (SI); 2) a second-order system; and 3) a double integrator. The analyses show that the HC utilizes a combined feedforward/feedback control strategy for all dynamics with the parabola target, and for the SI and second-order system with the ramp target. The feedforward model parameters are, however, very different between the two target waveform shapes, illustrating the adaptability of the HC to task variables. Moreover, strong evidence of anticipatory control behavior in the HC is found for the parabola target signal. The HC anticipates the future course of the parabola target signal given extensive practice, reflected by negative feedforward time delay estimates.

Haptic Guidance on Demand: A Grip-Force Based Scheduling of Guidance Forces.

In haptic shared control systems (HSC), a fixed strength of guidance force equates to a fixed level of control authority, which can be insufficient for complex tasks. An adaptable control authority based on operator input can allow the HSC system to better assist the operator under varied conditions. In this paper, we experimentally investigate () an adaptable authority HSC system that provides the operator with a direct way to adjust the control authority based on applied grip force. This system can serve as an intuitive 'manual override' function in case of HSC system malfunction. In a position tracking task, we explore two opposite approaches to adapt the control authority: increasing versus decreasing guidance strength with operator grip. These approaches were compared with unassisted control and two levels of fixed-level haptic guidance. Results show that the grip-adaptable approach allowed the operators to increase performance over unassisted control and over a weak guidance. At the same time, the approach substantially reduced the operator physical control effort required to cope with HSC system disturbances. Predictions based on the formalized model of the complete human-in-the-loop system corresponded to the experimental results, implying that such validated formalization can be used for model-based analysis and design of guidance systems.

What determines drivers' speed? A replication of three behavioural adaptation experiments in a single driving simulator study.

We conceptually replicated three highly cited experiments on speed adaptation, by measuring drivers' experienced risk (galvanic skin response; GSR), experienced task difficulty (self-reported task effort; SRTE) and safety margins (time-to-line-crossing; TLC) in a single experiment. The three measures were compared using a nonparametric index that captures the criteria of constancy during self-paced driving and sensitivity during forced-paced driving. In a driving simulator, 24 participants completed two forced-paced and one self-paced run. Each run held four different lane width conditions. Results showed that participants drove faster on wider lanes, thus confirming the expected speed adaptation. None of the three measures offered persuasive evidence for speed adaptation because they failed either the sensitivity criterion (GSR) or the constancy criterion (TLC, SRTE). An additional measure, steering reversal rate, outperformed the other three measures regarding sensitivity and constancy, prompting a further evaluation of the role of control activity in speed adaptation. Practitioner Summary: Results from a driving simulator experiment suggest that it is not experienced risk, experienced effort or safety margins that govern drivers' choice of speed. Rather, our findings suggest that steering reversal rate has an explanatory role in speed adaptation.

Admittance-Adaptive Model-Based Approach to Mitigate Biodynamic Feedthrough.

Biodynamic feedthrough (BDFT) refers to the feedthrough of vehicle accelerations through the human body, leading to involuntary control device inputs. BDFT impairs control performance in a large range of vehicles under various circumstances. Research shows that BDFT strongly depends on adaptations in the neuromuscular admittance dynamics of the human body. This paper proposes a model-based approach of BDFT mitigation that accounts for these neuromuscular adaptations. The method was tested, as proof-of-concept, in an experiment where participants inside a motion simulator controlled a simulated vehicle through a virtual tunnel. Through evaluating tracking performance and control effort with and without motion disturbance active and with and without cancellation active, the effectiveness of the cancellation was evaluated. Results show that the cancellation approach is successful: the detrimental effects of BDFT were largely removed.

Biorefinery of the green seaweed Ulva lactuca to produce animal feed, chemicals and biofuels.

The growing world population demands an increase in animal protein production. Seaweed may be a valuable source of protein for animal feed. However, a biorefinery approach aimed at cascading valorisation of both protein and non-protein seaweed constituents is required to realise an economically feasible value chain. In this study, such a biorefinery approach is presented for the green seaweed Ulva lactuca containing 225 g protein (N × 4.6) kg-1 dry matter (DM). The sugars in the biomass were solubilised by hot water treatment followed by enzymatic hydrolysis and centrifugation resulting in a sugar-rich hydrolysate (38.8 g L-1 sugars) containing glucose, rhamnose and xylose, and a protein-enriched (343 g kg-1 in DM) extracted fraction. This extracted fraction was characterised for use in animal feed, as compared to U. lactuca biomass. Based on the content of essential amino acids and the in vitro N (85 %) and organic matter (90 %) digestibility, the extracted fraction seems a promising protein source in diets for monogastric animals with improved characteristics as compared to the intact U. lactuca. The gas production test indicated a moderate rumen fermentation of U. lactuca and the extracted fraction, about similar to that of alfalfa. Reduction of the high content of minerals and trace elements may be required to allow a high inclusion level of U. lactuca products in animal diets. The hydrolysate was used successfully for the production of acetone, butanol, ethanol and 1,2-propanediol by clostridial fermentation, and the rhamnose fermentation pattern was studied.

A framework for biodynamic feedthrough analysis--part II: validation and application.

Biodynamic feedthrough (BDFT) is a complex phenomenon, that has been studied for several decades. However, there is little consensus on how to approach the BDFT problem in terms of definitions, nomenclature, and mathematical descriptions. In this paper, the framework for BDFT analysis, as presented in Part I of this dual publication, is validated and applied. The goal of this framework is twofold. First of all, it provides some common ground between the seemingly large range of different approaches existing in BDFT literature. Secondly, the framework itself allows for gaining new insights into BDFT phenomena. Using recently obtained measurement data, parts of the framework that were not already addressed elsewhere, are validated. As an example of a practical application of the framework, it will be demonstrated how the effects of control device dynamics on BDFT can be understood and accurately predicted. Other ways of employing the framework are illustrated by interpreting the results of three selected studies from the literature using the BDFT framework. The presentation of the BDFT framework is divided into two parts. This paper, Part II, addresses the validation and application of the framework. Part I, which is also published in this journal issue, addresses the theoretical foundations of the framework. The work is presented in two separate papers to allow for a detailed discussion of both the framework's theoretical background and its validation.

A framework for biodynamic feedthrough analysis--part I: theoretical foundations.

Biodynamic feedthrough (BDFT) is a complex phenomenon, which has been studied for several decades. However, there is little consensus on how to approach the BDFT problem in terms of definitions, nomenclature, and mathematical descriptions. In this paper, a framework for biodynamic feedthrough analysis is presented. The goal of this framework is two-fold. First, it provides some common ground between the seemingly large range of different approaches existing in the BDFT literature. Second, the framework itself allows for gaining new insights into BDFT phenomena. It will be shown how relevant signals can be obtained from measurement, how different BDFT dynamics can be derived from them, and how these different dynamics are related. Using the framework, BDFT can be dissected into several dynamical relationships, each relevant in understanding BDFT phenomena in more detail. The presentation of the BDFT framework is divided into two parts. This paper, Part I, addresses the theoretical foundations of the framework. Part II, which is also published in this issue, addresses the validation of the framework. The work is presented in two separate papers to allow for a detailed discussion of both the framework's theoretical background and its validation.

DNA Methylation.

The DNA of Escherichia coli contains 19,120 6-methyladenines and 12,045 5-methylcytosines in addition to the four regular bases, and these are formed by the postreplicative action of three DNA methyltransferases. The majority of the methylated bases are formed by the Dam and Dcm methyltransferases encoded by the dam (DNA adenine methyltransferase) and dcm (DNA cytosine methyltransferase) genes. Although not essential, Dam methylation is important for strand discrimination during the repair of replication errors, controlling the frequency of initiation of chromosome replication at oriC, and the regulation of transcription initiation at promoters containing GATC sequences. In contrast, there is no known function for Dcm methylation, although Dcm recognition sites constitute sequence motifs for Very Short Patch repair of T/G base mismatches. In certain bacteria (e.g., Vibrio cholerae, Caulobacter crescentus) adenine methylation is essential, and, in C. crescentus, it is important for temporal gene expression, which, in turn, is required for coordinating chromosome initiation, replication, and division. In practical terms, Dam and Dcm methylation can inhibit restriction enzyme cleavage, decrease transformation frequency in certain bacteria, and decrease the stability of short direct repeats and are necessary for site-directed mutagenesis and to probe eukaryotic structure and function.

A biodynamic feedthrough model based on neuromuscular principles.

A biodynamic feedthrough (BDFT) model is proposed that describes how vehicle accelerations feed through the human body, causing involuntary limb motions and so involuntary control inputs. BDFT dynamics strongly depend on limb dynamics, which can vary between persons (between-subject variability), but also within one person over time, e.g., due to the control task performed (within-subject variability). The proposed BDFT model is based on physical neuromuscular principles and is derived from an established admittance model-describing limb dynamics-which was extended to include control device dynamics and account for acceleration effects. The resulting BDFT model serves primarily the purpose of increasing the understanding of the relationship between neuromuscular admittance and biodynamic feedthrough. An added advantage of the proposed model is that its parameters can be estimated using a two-stage approach, making the parameter estimation more robust, as the procedure is largely based on the well documented procedure required for the admittance model. To estimate the parameter values of the BDFT model, data are used from an experiment in which both neuromuscular admittance and biodynamic feedthrough are measured. The quality of the BDFT model is evaluated in the frequency and time domain. Results provide strong evidence that the BDFT model and the proposed method of parameter estimation put forward in this paper allows for accurate BDFT modeling across different subjects (accounting for between-subject variability) and across control tasks (accounting for within-subject variability).

Mathematical biodynamic feedthrough model applied to rotorcraft.

Biodynamic feedthrough (BDFT) occurs when vehicle accelerations feed through the human body and cause involuntary control inputs. This paper proposes a model to quantitatively predict this effect in rotorcraft. This mathematical BDFT model aims to fill the gap between the currently existing black box BDFT models and physical BDFT models. The model structure was systematically constructed using asymptote modeling, a procedure described in detail in this paper. The resulting model can easily be implemented in many typical rotorcraft BDFT studies, using the provided model parameters. The model's performance was validated in both the frequency and time domain. Furthermore, it was compared with several recent BDFT models. The results show that the proposed mathematical model performs better than typical black box models and is easier to parameterize and implement than a recent physical model.

Identification of the feedforward component in manual control with predictable target signals.

In the manual control of a dynamic system, the human controller (HC) often follows a visible and predictable reference path. Compared with a purely feedback control strategy, performance can be improved by making use of this knowledge of the reference. The operator could effectively introduce feedforward control in conjunction with a feedback path to compensate for errors, as hypothesized in literature. However, feedforward behavior has never been identified from experimental data, nor have the hypothesized models been validated. This paper investigates human control behavior in pursuit tracking of a predictable reference signal while being perturbed by a quasi-random multisine disturbance signal. An experiment was done in which the relative strength of the target and disturbance signals were systematically varied. The anticipated changes in control behavior were studied by means of an ARX model analysis and by fitting three parametric HC models: two different feedback models and a combined feedforward and feedback model. The ARX analysis shows that the experiment participants employed control action on both the error and the target signal. The control action on the target was similar to the inverse of the system dynamics. Model fits show that this behavior can be modeled best by the combined feedforward and feedback model.

A qRT-PCR assay for the expression of all Mal d 1 isoallergen genes.

BACKGROUND: A considerable number of individuals suffer from oral allergy syndrome (OAS) to apple, resulting in the avoidance of apple consumption. Apple cultivars differ greatly in their allergenic properties, but knowledge of the causes for such differences is incomplete. Mal d 1 is considered the major apple allergen. For Mal d 1, a wide range of isoallergens and variants exist, and they are encoded by a large gene family. To identify the specific proteins/genes that are potentially involved in the allergy, we developed a PCR assay to monitor the expression of each individual Mal d 1 gene. Gene-specific primer pairs were designed for the exploitation of sequence differences among Mal d 1 genes. The specificity of these primers was validated using both in silico and in vitro techniques. Subsequently, this assay was applied to the peel and flesh of fruits from the two cultivars 'Florina' and 'Gala'. RESULTS: We successfully developed gene-specific primer pairs for each of the 31 Mal d 1 genes and incorporated them into a qRT-PCR assay. The results from the application of the assay showed that 11 genes were not expressed in fruit. In addition, differential expression was observed among the Mal d 1 genes that were expressed in the fruit. Moreover, the expression levels were tissue and cultivar dependent. CONCLUSION: The assay developed in this study facilitated the first characterisation of the expression levels of all known Mal d 1 genes in a gene-specific manner. Using this assay on different fruit tissues and cultivars, we obtained knowledge concerning gene relevance in allergenicity. This study provides new perspectives for research on both plant breeding and immunotherapy.