Journal articles on the topic 'Relative puese duration of the control signal'

Introduction: When diagnosing the deviations of controllable dynamic system parameters, it is convenient in terms of control simplicity to apply the Schreiber method which uses a set of rectangular pulses of equal duration as a test signal. Since for a single object you can construct many test signals which differ in the number of pulses, the problem arises how to minimize the number of test pulses when using the Schreiber method. Purpose: Simplification of test control and diagnostics of linear controllable dynamic systems. Results: It has been shown that a set of test pulse amplitude vectors is a kernel of the controllability matrix of a discrete analogue of the object under test. The problem is formulated of finding the optimal length of a test pulse in order to minimize the number of pulses in the test signal. For a given pulse length, the pulse amplitudes of an optimal test signal are equal to the coefficients of the control vector minimal polynomial for the discrete analog of the object relative to its system matrix. The number of test pulses can be reduced by choosing the pulse duration calculated from the imaginary component of the object poles. In particular, if an object has at least one pair of complex-conjugate poles, the number of test pulses does not at least exceed the order of the object. An algorithm has been developed for calculating a test signal for linear controllable object FDI by the Schreiber method. The input to the algorithm is the system matrix of the object, and the output is the length of the test pulse and the pulse amplitude vector. The efficiency of the algorithm is illustrated by FDI for two technical objects. Practical relevance: The results of the study can be applied to static parameter FDI of controllable dynamical objects which allow a linear description in their state space.

A stable 50-mJ three-channel optical waveform synthesizer is demonstrated and used to reproducibly generate a high-order harmonic supercontinuum in the soft x-ray region. This synthesizer is composed of pump pulses from a 10-Hz repetition-rate Ti:sapphire pump laser and signal and idler pulses from an infrared two-stage optical parametric amplifier driven by this pump laser. With full active stabilization of all relative time delays, relative phases, and the carrier-envelope phase, a shot-to-shot stable intense continuum harmonic spectrum is obtained around 60 eV with pulse energy above 0.24 μJ. The peak power of the soft x-ray continuum is evaluated to be beyond 1 GW with a 170-as transform limit duration. We found a characteristic delay dependence of the multicycle waveform synthesizer and established its control scheme. Compared with the one-color case, we experimentally observe an enhancement of the cutoff spectrum intensity by one to two orders of magnitude using three-color waveform synthesis.

Electropneumatic valves are a key element of the electropneumatic clutch control system for vehicles of categories N3 and M3. The speed and accuracy of the clutch control system depend on their parameters. When the operating conditions of the solenoid valve change, its initial parameters also change, even before the loss of serviceability. Goal. The goal of the work is to form dependencies that determine the parameters of the control signal for the clutch control system of vehicles of categories M3 and N3 in the conditions of change of supply voltage, pressure drop on the valve and ambient temperature. Methodology. To achieve this goal, an advanced mathematical model and onedimensional optimization method were used to determine the optimal control effect on the electropneumatic valve of the clutch control system. Results. The block diagram of the control pulse in different modes of operation of the electropneumatic clutch control system is given. Based on the calculated data, the characteristic areas of operation of the electropneumatic valve are determined and the purpose for the optimization process is determined. Based on the defined range of data change and the accuracy of finding the optimal value, a rational optimization method is determined. By modeling the operation of the solenoid valve with parameters according to the chosen optimization method, the response surfaces were constructed relative to the control pulse depending on such parameters as supply voltage of the vehicle onboard network, ambient temperature and pressure drop on the solenoid valve. Originality. The error in the reproduction of the theoretical response surfaces based on the parameters of the clutch and the electronic control unit is also determined. Theoretical aspects for providing the required inductance of the solenoid valve coil are shown. Practical value. A method for determining the pressure drop on an electropneumatic valve is proposed. The method takes into account the change in pressure during operation of the clutch control system due to wear of the friction plate. The error in ensuring the duration of the control pulse due to the presence of hysteresis in the operation of the clutch and the executive control device is estimated.

In below-grade buildings and buried structures, such as those constructed as hardened secure facilities and used for munitions storage on U.S. Army installations, water intrusion can cause serious damage and reduce penetration resistance. Inside the building active water and high humidity can result in corrosion of HVAC, electronic equipment, as well as damage or disrupt mission critical electronic equipment. In the adjacent backfill and the structure itself, excessive water can seriously compromise the structural hardening of the facility. Thus, it is vital to Army sustainability to control moisture in below-grade structures and eliminate corrosion of electrical mechanical equipment. This also prevents mold growth on the interior surface of below grade concrete walls and floors. Control of water movement involves both actively removing water in and around a building, and the use of barriers to prevent water from penetrating to interior spaces. A pumping system is typically required with the use of a barrier system to assist in controlling the movement of moisture into the structure. Conventional waterproofing technologies are expensive and often have short service life. A new approach is needed—a cost effective and robust solution—to the pervasive problem of water intrusion. Electro-Osmotic Pulse is a promising alternative solution presented here. Electro-Osmotic Pulse (EOP) technology uses pulses of electricity to reverse the flow of water seepage. The applied voltage causes moisture to flow out of the basement walls and away from the building. The technology works by alternately pulsating a direct electric field with an off period. The first part of the sequence consists of a pulse of positive voltage (as seen from the dry side of the concrete wall), followed by a pulse of negative voltage. This is followed by a period when no voltage is applied. Of the three parts, the positive voltage pulse has the greatest time duration. The amplitude of the positive signal is typically on the order of 20 to 40 Volts DC. This electrical pulse causes cations (e.g., Ca++) and associated water molecules to move from the dry side (anode) towards the wet side (cathode) against the direction of flow induced by the hydraulic gradient, thus preventing water penetration through buried concrete structures. Laboratory and field tests have shown an increase in calcium compounds at the cathode side of test specimens. The negative portion of the pulse increases the efficiency of moisture movement by depolarizing the electrodes. Electro-Osmotic Pulse (EOP) technology has been successfully installed in military structures such as family housing, steel reinforced deep structures, and tunnels. EOP has also been implemented on Civilian structures such as residential structures, D.C. Metro Tunnels, and an underground treasury vault. EOP has been shown to prevent moisture seepage into below-grade structures. It is effective at keeping concrete surfaces at or below 50 percent humidity content, meaning the treated space stays dry, indoor relative humidity stays low, and no mold or mildew can grow. This technology has received the 2002 international NOVA award for innovation in construction, and twice nominated for the CERF Pankow award (1999 and 2004). The ERDC research on this technology has also been recognized by the 2004 Army Research and Development Achievement Award.

Abstract In this paper, we study the diagnostics and identification of injection duration of common rail (CR) diesel pilot injectors of dual-fuel engines. In these pilot injectors, the injected volume is small and the repeatability of the injections and identification of the drifts of the injectors are important factors, which need to be taken into account in achieving good repeatability (shot-to-shot with every cylinder) and therefore a well-balanced engine and reduced overall wear. A diagnostics method based on analysis of CR pressure signal with experimental verification results is presented. Using the developed method, the relative duration of injection events can be identified. In the method, the pressure signal during the injection is first extracted after the control of each injection event. After that, the signal is normalized and filtered. Then a derivative of the filtered signal is calculated. Change in the derivative of the filtered signal larger than a predefined threshold indicates an injection event which can be detected and its relative duration can be identified. The efficacy of the proposed diagnostics method is presented with the experimental results, which show that the developed method detects drifts in injection duration and the magnitude of drift. According to the result, ≥ 10 μs change (2%, 500 μs) in injection time can be identified.

Electromyographic (EMG) and kinematic data were collected from European starlings (Sturnus vulgaris) flying at a range of speeds from 8 to 18 m s-1 in a variable-speed windtunnel. Their flight at all speeds consisted of alternating flapping and non-flapping phases. Wing postures during non-flapping phases included glides, partial-bounds and bounds. Glides were performed proportionally more often within each speed and were longer in duration than either of the other two non-flapping postures, but the percentage of bounds increased markedly with increasing flight speed. The shift from flap-gliding at slow speeds towards flap-bounding at fast speeds was consistent with reducing mean power output relative to continuous flapping. The starlings often combined more than one non-flapping posture within a single non-flapping period. Transitions between non-flapping postures, as well as transitions between bounds and subsequent flapping, were classified as 'pull-outs'. Pull-outs consisted of an increase in wingspan but no change in wingtip elevation. The pectoralis and supracoracoideus exhibited electrical activity during glides but not during bounds. The scapulohumeralis caudalis was not active during glides, but this muscle and the supracoracoideus were typically active during partial-bounds and pull-out phases. The scapulohumeralis caudalis occasionally showed activity during bounds, which may reflect its role as a humeral retractor. The frequency and duration of non-flapping intervals in starlings were less during EMG experiments than during non-implanted flights. During flapping phases, relative intensity and duration of EMG signal and wingbeat frequency increased with flight speed, whereas flapping or non-flapping cycle duration, the percentage of a cycle spent flapping and the number of wingbeats in a cycle were all greatest at 8 m s-1. Wingbeat amplitude was smaller at intermediate speeds, but differences among speeds were not significant. These variables allowed indirect estimates of power output and suggested that minimum power speed for starlings was near 12 m s-1 and that power output increased at both slower and faster speeds. Within windtunnel speeds, muscle activity changed in relation to wingspan at mid-upstroke, wingtip excursion, wingbeat frequency, acceleration, velocity, altitude and horizontal position.

Oximeters used for continuous monitoring experience periods with no signal. This SpO2drop-out is widely acknowledged and its causes generally understood. This is a prospectively designed analysis of an existing database with the aim of characterizing drop-outs as experienced in the neonatal ICU. The data reflects 116 days of monitoring in seven tertiary care neonatal ICUs in 6 countries. From the evaluation of 1,396 drop-outs we found that typically the time was minimal with missing SpO2 data, and the episodes were short (median 2.79 minutes per day IQR 0.17-76, median 22 seconds IQR: 15-37, respectively). During during about half of the days there were no prolonged dropouts (1 minute or longer), even so half of the total time spent with no SpO2data were in prolonged episodes (median length 110 seconds IQR 85-150). The predominate factor associated with excessive drop-out time was the number of prolonged episodes rather than their duration. We concluded that the impact of drop-outs during manual control of inspired oxygen primarily impact alarm fatigue, but that during automatic FiO2control they could have an important impact. The relative effectiveness of the fall-back strategies of these automatic control systems ought to be evaluated.

Understanding how orofacial muscle activity and movement covary across changes in speech rate and intensity has implications for the neural control of speech production and the use of clinical procedures that manipulate speech prosody. The present study involved a correlation analysis relating average lower-lip and jaw-muscle activity to lip and jaw movement distance, speed, and duration. Recordings were obtained on orofacial movement, muscle activity, and the acoustic signal in 3 normal speakers as they repeated a simple test utterance with targeted speech rates varying from 60% to 160% of their habitual rate and at targeted vocal intensities of –6 dB and +6 dB relative to their habitual intensity. Surface electromyographic (EMG) recordings were obtained with electrodes positioned to sample primarily the mentalis, depressor labii inferior, anterior belly of the digastric, and masseter muscles. Two-dimensional displacements of the lower lip and jaw in the midsagittal plane were recorded with an electromagnetic system. All participants produced linear changes in percent utterance duration relative to the auditory targets for speech rate variation. Intensity variations ranged from –10 dB to +8 dB. Average EMG levels for all 4 muscles were well correlated with specific parameters of movement. Across the intensity conditions, EMG level was positively correlated with movement speed and distance in all participants. Across the rate conditions, EMG level was negatively correlated with movement duration in all participants, while greater interparticipant variability was noted for correlations relating EMG to speed and distance. For intensity control, it is suggested that converging neural input to orofacial motoneurons varies monotonically with movement distance and speed. In contrast, rate control appears to be more strongly related to the temporal characteristics of neural input than activation level.

AbstractIntroductionHaemodynamically unstable patients can experience potentially hazardous changes in vital signs related to the exchange of depleted syringes of epinephrine to full syringes. The purpose was to determine the measured effects of epinephrine syringe exchanges on the magnitude, duration, and frequency of haemodynamic disturbances in the hour after an exchange event (study) relative to the hours before (control).Materials and methodsBeat-to-beat vital signs recorded every 2 seconds from bedside monitors for patients admitted to the paediatric cardiovascular ICU of Texas Children’s Hospital were collected between 1 January, 2013 and 30 June, 2015. Epinephrine syringe exchanges without dose/flow change were obtained from electronic records. Time, magnitude, and duration of changes in systolic blood pressure and heart rate were characterised using Matlab. Significant haemodynamic events were identified and compared with control data.ResultsIn all, 1042 syringe exchange events were found and 850 (81.6%) had uncorrupted data for analysis. A total of 744 (87.5%) exchanges had at least 1 associated haemodynamic perturbation including 2958 systolic blood pressure and 1747 heart-rate changes. Heart-rate perturbations occurred 37% before exchange and 63% after exchange, and 37% of systolic blood pressure perturbations happened before syringe exchange, whereas 63% occurred after syringe exchange with significant differences found in systolic blood pressure frequency (p<0.001), duration (p<0.001), and amplitude (p<0.001) compared with control data.ConclusionsThis novel data collection and signal processing analysis showed a significant increase in frequency, duration, and magnitude of systolic blood pressure perturbations surrounding epinephrine syringe exchange events.

We consider the task of automated quality control of sound recordings containing voice samples of individuals. It is shown that in this task the most acute is the small sample size. In order to overcome this problem, we propose the novel method of acoustic measurements based on relative stability of the pitch frequency within a voice sample of short duration. An example of its practical implementation using aninter-periodic accumulation of a speech signal is considered. An experimental study with specially developed software provides statistical estimates of the effectiveness of the proposed method in noisy environments. It is shown that this method rejects the audio recording as unsuitable for a voice biometric identification with a probability of 0,95 or more for a signal to noise ratio below 15 dB. The obtained results are intended for use in the development of new and modifying existing systems of collecting and automated quality control of biometric personal data. The article is intended for a wide range of specialists in the field of acoustic measurements and digital processing of speech signals, as well as for practitioners who organize the work of authorized organizations in preparing for registration samples of biometric personal data.

This study examined the effects on sleep of light administered to an extraocular site. A 3-h photic stimulus was applied to the popliteal region during sleep in 14 human subjects. Each subject also underwent a control stimulus condition during a separate laboratory session. The proportion of rapid eye movement (REM) sleep during the 3-h light administration session increased by an average of 31% relative to the control condition. The frequency but not the duration of REM episodes was altered during light exposure, thereby shortening the REM/non-REM (NREM) cycle length. No other sleep stages were significantly affected during light administration nor was sleep architecture altered after the light-exposure interval. These results confirm that extraocular light is transduced into a signal that is received and processed by the human central nervous system. In addition, they expand to a novel sensory modality previous findings that REM sleep can be enhanced by sensory stimulation.

Abstract The purpose of this study was to determine whether leptin induces leptin resistance by examining the temporal attenuation of the anorexic and energy expenditure responses to leptin. We administered recombinant adeno-associated virus encoding rat leptin cDNA or control viral vector into mildly obese rats for 138 d and compared these results with those from pair-fed rats. We measured food consumption, body weight, oxygen consumption, leptin signal transduction, and brown adipose tissue uncoupling protein 1. The anorexic response attenuated by d 25, whereas the increase in energy expenditure persisted for 83 d before attenuating. Despite attenuation of physiological responses, phosphorylated signal transducer and activator of transcription-3 remained elevated for the duration of the study. The temporal differential attenuation of the anorexic and thermogenic responses allowed us to determine the relative contributions of each response to weight maintenance. The anorexic response predominantly mediated the initial loss of body weight, but only the energy expenditure response was necessary to maintain the reduced weight. This study provides evidence that leptin induces leptin resistance. The leptin resistance was associated with persistent elevation in hypothalamic phosphorylated signal transducer and activator of transcription-3 and was characterized by a rapid attenuation of the anorexic response and slower onset for the attenuation of the energy expenditure response. We propose that both elevated leptin and obesity may be necessary for the development of leptin resistance.

Purpose – The paper aims to theoretically and experimentally investigate vibratory peg-bush alignment using elastic vibrations of the peg, when the peg is axially excited by a pressed piezoelectric vibrator on the upper end. Design/methodology/approach – Experimental research of part alignment using elastic vibrations was performed and dependencies of alignment duration on excitation signal parameters and initial pressing force were defined for rectangular and circular cross-section parts. Mathematical model of two-mass dynamic systems with elastic contact model representing alignment process was created. Dependencies of system parameters on the alignment duration were obtained by numerically solving systems differential equations. Findings – Theoretical and experimental investigation approved the usage of elastic vibrations for alignment of chamferless circular and rectangular cross-section parts. This novel method of part alignment compensates axial misalignment between mating parts by directional displacement of movably based bush. Research limitations/implications – Impact and non-impact interaction between bush and peg is possible; however, only non-impact regime was investigated. Static and dynamic coefficients of friction between the parts are equivalent and do not depend on relative velocity of parts. Practical implications – The results are useful in designing reliable and effective assembly equipment with vibratory assistance alignment for peg-bush operations, which do not require auxiliary sensors and feedback systems. Use of a piezoelectric resonator for peg excitation makes this system easily adaptable to the existing automated assembly equipment. Originality/value – The proposed method is a new approach to vibratory alignment. The data obtained during investigation expand the insight of the physical processes that drive bush to the axial alignment direction.

When building autonomous real-time systems (RTS), it is necessary to solve the problem of optimal multitasking loading of a number of parallel functioning digital signal processors. One of the reserves for achieving the desired result is the implementation of samples from the sensor signals of information about the magnitude of the signal most rarely in time. In this case, it is necessary to provide a linear or stepwise approximation of the signal by samples with an acceptable reconstruction error. One of the system tasks of these processors is filtering signals or limiting the spectrum to the cutoff frequency. A distinctive feature of the approach proposed in the article is the fulfillment of the condition: if the measurement of this frequency is difficult (for example, in the electromechanical means of the RTS), then for such signals it is proposed to match the maximum values of the harmonic half-wave parameters: approximation error, speed and acceleration. The study opens up the prospect of applying new approaches to sampling the time of signals in the amplitude-time domain and determining the equivalent cutoff frequency of the signal spectrum for such signals. In this article, the dependences of the value of the unit of system time for input-output of data on the degree of agreement between the maximum values of the signal parameters are obtained. A mathematical model of the extreme behavior of a signal between two adjacent samples is given in the form of a harmonic half-wave. The study is also extended to convex composite harmonic functions, according to which the signal can deviate from the results of a linear or stepwise approximation of the signal for these samples. The comparison of the models by the value of the relative time sampling intervals, depending on the degree of matching of the maximum parameters of the harmonic half-wave, is carried out. When comparing, in addition to these maximum parameters, the relationship of the maximum signal speed with the error of approximating the samples by steps and the relationship of the maximum acceleration of the signal with the maximum error of the linear approximation was taken into account. The results make it possible to determine the duration of the intervals of uniform sampling of the signal time based on the results of the inspection of the control object, substantiate a significant increase in the sampling interval of time or a similar increase in the number of tasks to be solved per unit of system time.

Accurate sensory processing during movement requires the animal to distinguish between external (exafferent) and self-generated (reafferent) stimuli to maintain sensitivity to biologically relevant cues. The lateral line system in fishes is a mechanosensory organ that experiences reafferent sensory feedback, via detection of fluid motion relative to the body generated during behaviors such as swimming. For the first time in larval zebrafish ( Danio rerio), we employed simultaneous recordings of lateral line and motor activity to reveal the activity of afferent neurons arising from endogenous feedback from hindbrain efferent neurons during locomotion. Frequency of spontaneous spiking in posterior lateral line afferent neurons decreased during motor activity and was absent for more than half of swimming trials. Targeted photoablation of efferent neurons abolished the afferent inhibition that was correlated to swimming, indicating that inhibitory efferent neurons are necessary for modulating lateral line sensitivity during locomotion. We monitored calcium activity with Tg(elav13:GCaMP6s) fish and found synchronous activity between putative cholinergic efferent neurons and motor neurons. We examined correlates of motor activity to determine which may best predict the attenuation of afferent activity and therefore what components of the motor signal are translated through the corollary discharge. Swim duration was most strongly correlated to the change in afferent spike frequency. Attenuated spike frequency persisted past the end of the fictive swim bout, suggesting that corollary discharge also affects the glide phase of burst and glide locomotion. The duration of the glide in which spike frequency was attenuated increased with swim duration but decreased with motor frequency. Our results detail a neuromodulatory mechanism in larval zebrafish that adaptively filters self-generated flow stimuli during both the active and passive phases of locomotion. NEW & NOTEWORTHY For the first time in vivo, we quantify the endogenous effect of efferent activity on afferent gain control in a vertebrate hair cell system during and after locomotion. We believe that this pervasive effect has been underestimated when afferent activity of octavolateralis systems is characterized in the current literature. We further identify a refractory period out of phase with efferent control and place this gain mechanism in the context of gliding behavior of freely moving animals.

The proposed work is the first part of the overall work on the development of the structure of the hydroacoustic navigation system (HNST) for bringing the autonomous underwater vehicle (AUV) to the docking module (DM). The second (final) part will be published in the next issue of the journal. The purpose of this work is to select signals for building HNST providing reduction in a near zone at the distances not exceeding 300 m, an AUV and its docking with the carrier is considered. Mutual definition of a distance and angular position DM of the carrier and AUV relative to each other is carried out for this purpose. Determination of mutual angular coordinates can be carried out with use of HNST with short and ultra-short base. HNST with short base is preferable for realization from the point of view of simplicity. However, its installation on the AUV can be impossible because of rather small sizes of the device, and on AUV should be installed HNST with ultra-short base. HNST with short base can be established on the docking module. Since there are no reasons to assume the high speed of change of the phase characteristic of the developed high-frequency channel of transformation therefore the interval of stationarity of the phase characteristic should be significantly more than duration of a symbol at a speed of transfer of 4 kBit/s. Therefore, it is advisable to exchange measurement data between AUV and DM in the composition of HNST by relative phase modulation (DPSM). Reception of signals is performed by a suboptimal incoherent receiver on which entrance deep restriction of an entrance signal is carried out. The use of deep signal limitation at the receiver input allows to exclude operation of automatic control of strengthening at a stage of entry into communication, as a result, it is possible to reduce the duration of communication sessions. In the combined information navigation system, it is expedient: to apply as navigation signals of data exchanged between AUV and DM based on the results of mutual measurement of navigation parameters; to carry out data exchange between AUV and DM by method DPSM with a speed V = 4 kBit/s; to carry out transfer of the block of data with application of the correcting block cyclic code ; to apply to reception of a block of data diversity reception in combination with majority decoding characters, and then correct errors in the data block with the help of code, and to accompany the issuance of data to the user sign detection code errors in the block.

Purpose The purpose of this study was to compare Words-in-Noise (WIN) data between young adults with perinatal HIV (PHIV) infection and those with PHIV exposure but uninfected (PHEU) and to evaluate associations between antiretroviral therapy (ART) exposures and WIN data. Method The WIN test and cognitive function were assessed in participants of the Pediatric HIV/AIDS Cohort Study Adolescent Master Protocol Up. Impaired WIN (IWIN) performance was defined as a signal-to-babble ratio of > +10 dB. Cognitive function was determined based on fluid cognition composite scores (FCCSs) and crystallized cognition composite scores, and < 70 was considered a fluid or crystallized cognitive impairment. Log binomial models were used to calculate the relative risks of IWIN between PHIV and PHEU. Results PHIV ( n = 334) and PHEU ( n = 52) participants had similar WIN thresholds and IWIN percentages. For young adults with FCCS ≥ 70, participants with PHIV were less likely to have IWIN for the better ear and worse ear as compared to participants with PHEU. For young adults with FCCS < 70, there was no association between HIV status and risk of IWIN for the better ear or worse ear. For those adults with crystallized cognition composite score of ≥ 70, young adults with PHIV were less likely to have IWIN for the better ear than young adults with PHEU; there was no association between HIV status and IWIN for the worse ear. For young adults with PHIV without a Centers for Disease Control and Prevention Class C diagnosis, a longer combination ART duration was associated with a higher risk of IWIN for the better ear. Conclusions For those without cognitive impairment, young adults with PHEU had poorer WIN thresholds than those young adults with PHIV. In young adults with PHIV who had no prior Centers for Disease Control and Prevention Class C diagnosis, a longer combination ART duration was associated with IWIN only in the better ear.

Abstract Monocyte-derived lipid-containing macrophages (MDLMs) constitutively synthesize a granulomonopoietic enhancing activity (GM-EA) that potentiates the function of granulocyte-macrophage colony-stimulating activity (GM-CSA). In the study reported, we show that GM-EA is distinct from interleukin-1 (IL-1) in biochemical and functional properties and that its production is negatively regulated by several mediators. Thus, MDLM cultures pretreated with interferon-gamma (IFN- gamma, 3 to 900 U/mL), prostaglandin E2 (PGE2, 10(-13) to 10(-8) mol/L), or lactoferrin (LF, 10(-13) to 10(-8) mol/L) invariably produced less GM-EA than untreated controls. The relative potency of inhibition was in the order of IFN-gamma greater than or equal to PGE2 greater than LF. The extent of the inhibitory effects was proportional to dosage and the duration of treatment and could be observed following only a brief exposure (two hours) of the MDLMS to physiologic doses of the mediators. Under optimal conditions, IFN-gamma (300 U/mL for 24 to 48 hours) and PGE2 (10(-9) mol/L for 24 to 48 hours) could totally abrogate the ability of the MDLMs to produce GM-EA. However, the drug- inhibited MDLMs could be reactivated to produce GM-EA by treatment with zymosan (60 micrograms/mL). These results demonstrate that a mechanism for the control of myelopoiesis by mediators such as IFN-gamma, PGE2, and LF may involve the inhibition of GM-EA production. Furthermore, this negative feedback control is reversible and can be overridden when a proper stimulatory signal is given.

Monocyte-derived lipid-containing macrophages (MDLMs) constitutively synthesize a granulomonopoietic enhancing activity (GM-EA) that potentiates the function of granulocyte-macrophage colony-stimulating activity (GM-CSA). In the study reported, we show that GM-EA is distinct from interleukin-1 (IL-1) in biochemical and functional properties and that its production is negatively regulated by several mediators. Thus, MDLM cultures pretreated with interferon-gamma (IFN- gamma, 3 to 900 U/mL), prostaglandin E2 (PGE2, 10(-13) to 10(-8) mol/L), or lactoferrin (LF, 10(-13) to 10(-8) mol/L) invariably produced less GM-EA than untreated controls. The relative potency of inhibition was in the order of IFN-gamma greater than or equal to PGE2 greater than LF. The extent of the inhibitory effects was proportional to dosage and the duration of treatment and could be observed following only a brief exposure (two hours) of the MDLMS to physiologic doses of the mediators. Under optimal conditions, IFN-gamma (300 U/mL for 24 to 48 hours) and PGE2 (10(-9) mol/L for 24 to 48 hours) could totally abrogate the ability of the MDLMs to produce GM-EA. However, the drug- inhibited MDLMs could be reactivated to produce GM-EA by treatment with zymosan (60 micrograms/mL). These results demonstrate that a mechanism for the control of myelopoiesis by mediators such as IFN-gamma, PGE2, and LF may involve the inhibition of GM-EA production. Furthermore, this negative feedback control is reversible and can be overridden when a proper stimulatory signal is given.

Abstract. Response of renal vasculature to changes in renal perfusion pressure (RPP) involves mechanisms with different frequency characteristics. Autoregulation of renal blood flow is mediated by a rapid myogenic response and a slower tubuloglomerular feedback mechanism. In 25 male conscious rats, ramp-shaped changes in RPP were induced to quantify dynamic properties of autoregulation. Decremental RPP ramps immediately followed by incremental ramps were made for four different rates of change, ranging from 0.118 to 1.056 mmHg/s. Renal blood flow and cortical and medullary fluxes were assessed, and the corresponding relative conductance values were calculated continuously. During RPP decrements, conductance increased. With increasing rate of change of RPP decrements, maximum conductance increased from 10% to 80%, as compared with control. This response, which indicates the magnitude of autoregulation, was more pronounced in cortical versus medullary vasculature. Pressure at maximum conductance decreased with increasing rate of change of RPP decrements from 88 to 72 mmHg. During RPP increments, dependence of maximum conductance changes on the rate of change was enhanced (-20 to 110% of control). Thus, a hysteresis-like asymmetry between RPP decrements and increments, a resetting of autoregulation, was observed, which in direction and magnitude depended on the rate of change and duration of RPP changes. In conclusion, renal vascular responses to changes in RPP are highly dependent on the dynamics of the error signal. Furthermore, the method presented allows differentiated stimulation of various static and dynamic components of pressure-flow relationship and, thus, a direct assessment of the magnitudes and operating pressure range of active mechanisms of pressure-flow relationships.

During sepsis, growth hormone (GH) resistance contributes to the catabolism of muscle protein. To determine the role of tumor necrosis factor (TNF) as a mediator of GH resistance, we examined the effects of a TNF antagonist [TNF-binding protein (TNFbp)] on the GH/insulin-like growth factor (IGF) I system during abdominal sepsis. To investigate potential mechanisms, the effects of TNF on the IGF-I response to GH and GH signaling were examined in cultured rat hepatocytes (CWSV-1). Three groups of rats were studied: Control, Sepsis, and Sepsis + TNFbp. Liver, gastrocnemius, and plasma were collected on day 5. In gastrocnemius, neither sepsis nor TNFbp altered the abundance of IGF-I mRNA. However, septic rats demonstrated an increase in circulating GH and a reduction in plasma IGF-I concentrations that was ameliorated by pretreatment with TNFbp. Liver from septic rats demonstrated a 50% reduction in GH receptor (GHR) and IGF-I mRNA on day 5 that was attenuated by TNFbp. However, the abundance of GHR protein was not different in liver from Control, Sepsis, or Sepsis + TNFbp rats. Consequently, a decreased amount of hepatic GHR does not explain the GH-resistant septic state. In CWSV-1 hepatocytes, TNF-α had no effect on GHR protein level but inhibited the induction of IGF-I mRNA by GH. Nuclear protein from TNF-treated hepatocytes demonstrated similar levels of phosphorylated signal transducer and activator of transcription-5 (STAT5) and DNA binding relative to controls 5 min after GH treatment. However, both of these parameters were decreased (vs. control) in TNF-treated cells 60 min after GH treatment. Collectively, these results suggest that TNF mediates hepatic GH resistance during sepsis by inhibiting the duration of signaling via the janus kinase-2/STAT5 pathway.

Abstract. Detection of liquid-containing cloud layers in thick mixed-phase clouds or multi-layer cloud situations from ground-based remote-sensing instruments still poses observational challenges, yet improvements are crucial since the existence of multi-layer liquid layers in mixed-phase cloud situations influences cloud radiative effects, cloud lifetime, and precipitation formation processes. Hydrometeor target classifications such as from Cloudnet that require a lidar signal for the classification of liquid are limited to the maximum height of lidar signal penetration and thus often lead to underestimations of liquid-containing cloud layers. Here we evaluate the Cloudnet liquid detection against the approach of Luke et al. (2010) which extracts morphological features in cloud-penetrating cloud radar Doppler spectra measurements in an artificial neural network (ANN) approach to classify liquid beyond full lidar signal attenuation based on the simulation of the two lidar parameters particle backscatter coefficient and particle depolarization ratio. We show that the ANN of Luke et al. (2010) which was trained under Arctic conditions can successfully be applied to observations at the mid-latitudes obtained during the 7-week-long ACCEPT field experiment in Cabauw, the Netherlands, in 2014. In a sensitivity study covering the whole duration of the ACCEPT campaign, different liquid-detection thresholds for ANN-predicted lidar variables are applied and evaluated against the Cloudnet target classification. Independent validation of the liquid mask from the standard Cloudnet target classification against the ANN-based technique is realized by comparisons to observations of microwave radiometer liquid-water path, ceilometer liquid-layer base altitude, and radiosonde relative humidity. In addition, a case-study comparison against the cloud feature mask detected by the space-borne lidar aboard the CALIPSO satellite is presented. Three conclusions were drawn from the investigation. First, it was found that the threshold selection criteria of liquid-related lidar backscatter and depolarization alone control the liquid detection considerably. Second, all threshold values used in the ANN framework were found to outperform the Cloudnet target classification for deep or multi-layer cloud situations where the lidar signal is fully attenuated within low liquid layers and the cloud radar is able to detect the microphysical fingerprint of liquid in higher cloud layers. Third, if lidar data are available, Cloudnet is at least as good as the ANN. The times when Cloudnet outperforms the ANN in liquid detections are often associated with situations where cloud dynamics smear the imprint of cloud microphysics on the radar Doppler spectra.

Abstract-Methods for control of the content of non-meat components (connective tissue of animals, eggs, soybeans) in meat products have been developed based on competitive enzyme immunoassay of biomarker proteins: collagen, ovalbumin, and soybean trypsin inhibitor. Polyclonal rabbit antibodies against the biomarkers were produced. Screening of the following analysis conditions was carried out using the most affine preparations: the duration of the stages, the concentrations of the reagents, the composition of the reaction medium to ensure the completeness and the minimum limits of detection of analytes. It was shown that the immunochemical stage can be transferred to the kinetic mode and reduced to 20 min, while the total analysis took only 1 h. The selected conditions synchronized detection stages and provided the same signal amplitudes from all three biomarkers. An additional advantage of the method is that the analysis can be carried out at room temperature. The detection limits for collagen, ovalbumin and soybean trypsin inhibitor in the final extracts were 0.025 μg/mL, 0.012 μg/mL, and 0.001 μg/mL, respectively. Approbation of the method showed the reliability of the conclusions about the composition of the tested meat products; the relative standard deviation in the analysis of the monitored biomarkers was 8-10%. Key words: enzyme-linked immunoassay, meat products, collagen, ovalbumin, soybean trypsin inhibitor The work was financially supported by the Russian Science Foundation (project no. 19-16-00108).

Abstract Ubiquitination of lysine (K) residues in the cytoplasmic domain of cytokine receptors plays a major role in intracellular receptor routing and control of signal duration. However, which ubiquitin (E3) ligases and whether specific lysines, eg. present in conserved motifs, are involved in ubiquitin-mediated routing is still largely unknown. We recently showed that SOCS3, which forms an Elongin/Cullin-based E3 ligase (ECSSOCS3), is involved in ligand-induced ubiquitination, lysosomal routing and degradation of the G-CSFR (Irandoust et al, EMBO J. 2007, 26:1782–93). Strikingly, ECSSOCS3-mediated mechanisms largely depended on ubiquitination of a single juxtamembrane lysine at position 632 (K632), even though 4 additional conserved lysines are present in the cytoplasmic domain of the G-CSFR. This juxtamembrane lysine located 5 amino acids upstream of the box1 region is conserved among several other cytokine receptors. We sought to unravel the configuration required for ubiquitination of K632 and for its function in attenuation of G-CSF signaling. First, we tested whether K632 is part of a domain that can function as an isolated motif. To this end, we fused the K632-containing domain (D) encompassing the juxtamembrane and box1 regions to the COOH-terminus of a lysine-less G-CSFR (K5R-D). Despite efficient ubiquitination of the lysine within the reallocated domain, K5R-D, similar to K5R, was severely hampered in lysosomal routing. This resulted in prolonged STAT5 activation and in G-CSF-induced hyperproliferation of myeloid 32D cells indicating that the juxtamembrane domain of the G-CSFR does not function as an isolated domain that can be shifted to a different cytoplasmic location. To delineate how imperative the positioning of K632 is for its function, we inserted 5 alanines immediately upstream or downstream of K632. However, these insertions did not affect G-CSFR signal duration suggesting that there is no stringent proximity of K632 to the cell membrane and no strict positioning relative to the SOCS3 recuitment site (Y729) to direct downregulation of G-CSFR signaling. To further study this flexibility in positioning we ‘walked’ lysines through the juxtamembrane domain and the adjacent box 1-region by mutating amino acids at indicated positions to a lysine in an otherwise lysine-less G-CSFR. Mutants 628K and 630K were hardly ubiquitinated and, as predicted, were hampered in lysosomal routing. In contrast, lysines on position 631, 633, 634, 638 and 644 were ubiquitinated comparably to K632. Interestingly, while mutants 631K, 633K and 634K showed characteristics indistinguishable from 632K, mutants 638K and 644K displayed slightly decreased signal attenuation suggesting a gradual decline of functionality of lysines moved to box-1. Finally, moving the lysine downstream to position 672, which corresponds to the second lysine in the wt G-CSFR, resulted in complete loss of functionality. In conclusion, these results indicate that the positioning of a lysine within the juxtamembrane domain is crucial for ECSSOCS3-mediated signal downregulation and lysosomal routing of the G-CSFR, although a limited flexibility is tolerated towards the box1 region. The fact that inactive lysines are still ubiquitinated implies that interaction with effector proteins is involved in lysosomal routing rather than reduced or lost activity of E3 ligases. Given its high conservation among several cytokine receptors we are currently investigating a common role for the juxtamembrane lysine in cytokine receptor routing and signal attenuation.

AbstractStudies have examined listening effort in individuals with hearing loss to determine the extent of the impairment. Regarding cochlear implants (CIs), results suggest that listening effort is improved using bilateral CIs compared to unilateral CIs. Few studies have investigated listening effort and outcomes related to the hybrid CI.Here, we compared listening effort across three CI groups, and to a normal-hearing control group. The impact of listener traits, that is, age, age at onset of hearing loss, duration of CI use, and working memory capacity, were examined relative to listening effort.The participants completed a dual-task paradigm with a primary task identifying sentences in noise and a secondary task measuring reaction time on a Stroop test. Performance was assessed for all participant groups at different signal-to-noise ratios (SNRs), ranging in 2-dB steps from 0 to +10 dB relative to an individual’s SNR-50, at which the speech recognition performance is 50% correct. Participants completed three questions on listening effort, the Spatial Hearing Questionnaire, and a reading span test.All 46 participants were adults. The four participant groups included (1) 12 individuals with normal hearing, (2) 10 with unilateral CIs, (3) 12 with bilateral CIs, and (4) 12 with a hybrid short-electrode CI and bilateral residual hearing.Results from the dual-task experiment were compared using a mixed 4 (hearing group) by 6 (SNR condition) analysis of variance (ANOVA). Questionnaire results were compared using one-way ANOVAs, and correlations between listener traits and the objective and subjective measures were compared using Pearson correlation coefficients.Significant differences were found in speech perception among the normal-hearing and the unilateral and the bilateral CI groups. There was no difference in primary task performance among the hybrid CI and the normal-hearing groups. Across the six SNR conditions, listening effort improved to a greater degree for the normal-hearing group compared to the CI groups. However, there was no significant difference in listening effort between the CI groups. The subjective measures revealed significant differences between the normal-hearing and CI groups, but no difference among the three CI groups. Across all groups, age was significantly correlated with listening effort. We found no relationship between listening effort and the age at the onset of hearing loss, age at implantation, the duration of CI use, and working memory capacity for these participants.Listening effort was reduced to a greater degree for the normal-hearing group compared to the CI users. There was no significant difference in listening effort among the CI groups. For the CI users in this study, age was a significant factor with regard to listening effort, whereas other variables such as the duration of CI use and the age at the onset of hearing loss were not significantly related to listening effort.

Background: During the revision of the American National Standards Institute (ANSI) C63.19 and the development of the ANSI/Telecommunications Industry Association–1083 hearing aid compatibility standards, it became evident that additional data concerning user acceptance of interfering magnetic noises generated by wireless and cordless telephones were needed in order to determine the requirements for telecoil-coupling compatibility. Purpose: Further insight was needed into the magnetic signal-to-noise (S/N) ratios required to achieve specific levels of telephone usability by hearing aid wearers. (A companion article addresses magnetic signal level requirements.) Research Design: Test subjects used their own hearing aids. The magnetic signals were applied through large magnetic head-worn coils, selected for the field orientation appropriate for each hearing aid. After adjusting their aid's volume control to an acoustic speech reference, the subjects adjusted the applied magnetic signal level to find their Most Comfortable Level (MCL). Each subject then adjusted the levels of six of eight different representative interfering noises to three levels of subjective telephone usability: “usable for a brief call,” “acceptable for normal use,” and “excellent performance.” Each subject's objective noise audibility threshold in the presence of speech was also obtained for the various noise types. Study Sample: The 57 test subjects covered an age range of 22 to 79 yr, with a self-reported hearing loss duration of 12 to 72 yr. All had telecoils that they used for at least some telecommunications needs. The self-reported degree of hearing loss ranged from moderate to profound. Data Collection and Analysis: A guided intake questionnaire yielded general background information for each subject. A test control box fed by prepared speech and noise recordings from computer files enabled the subject or the tester, depending on the portion of the test, to select A-weighting-normalized noise interference levels in 1.25 dB steps relative to the selected MCL. For each subject for each tested noise type, the values for the selected S/N ratios were recorded for the three categories of subjective usability and the objective noise threshold. Results: About half of the test subjects needed a minimum 21 dB S/N ratio for them to consider their listening experience “acceptable for normal use” of a telephone. With a 30 dB S/N ratio, about 85% of the subjects reported normal use acceptability. Significant differences were apparent in the measured S/N user requirements among the noise types, though, indicating a deficiency in an A-weighted level measurement's ability to consistently predict the subjective acceptability of the various noises. An improved weighting function having both spectral and temporal components was developed to substantially eliminate these predictive inconsistencies. Conclusions: The interfering noise level that subjects chose for a telephone usability rating of “excellent performance” matched closely their objectively measured noise audibility threshold. A rating of “acceptable for normal use” was typically achieved at a 4 dB higher noise level, and a rating of “usable for a brief call,” at a 10.4 dB higher noise level. These results did not relate significantly to noise type or to the subject's aided noise-in-speech hearing acuity.

Autonomous vehicles are expected to take complete control of the driving process, enabling the former drivers to act as passengers only. This could lead to increased sickness as they can be engaged in tasks other than driving. Adopting different sickness mitigation techniques gives us unique types of motion sickness in autonomous vehicles to be studied. In this paper, we report on a study where we explored the possibilities of assessing motion sickness with electrogastrography (EGG), a non-invasive method used to measure the myoelectric activity of the stomach, and its potential usage in autonomous vehicles (AVs). The study was conducted in a high-fidelity driving simulator with a virtual reality (VR) headset. There separate EGG measurements were performed: before, during and after the driving AV simulation video in VR. During the driving, the participants encountered two driving environments: a straight and less dynamic highway road and a highly dynamic and curvy countryside road. The EGG signal was recorded with a proprietary 3-channel recording device and Ag/AgCl cutaneous electrodes. In addition, participants were asked to signalize whenever they felt uncomfortable and nauseated by pressing a special button. After the drive they completed also the Simulator Sickness Questionnaire (SSQ) and reported on their overall subjective perception of sickness symptoms. The EGG results showed a significant increase of the dominant frequency (DF) and the percentage of the high power spectrum density (FSD) as well as a significant decrease of the power spectrum density Crest factor (CF) during the AV simulation. The vast majority of participants reported nausea during more dynamic conditions, accompanied by an increase in the amplitude and the RMS value of EGG. Reported nausea occurred simultaneously with the increase in EGG amplitude. Based on the results, we conclude that EGG could be used for assessment of motion sickness in autonomous vehicles. DF, CF and FSD can be used as overall sickness indicators, while the relative increase in amplitude of EGG signal and duration of that increase can be used as short-term sickness indicators where the driving environment may affect the driver.

The late gestation fetal ECG (fECG) has traditionally been difficult to characterize due to the low fECG signal relative to high maternal noise. Although new technologies have improved the feasibility of its acquisition and separation, little is known about its development in late gestation, a period in which the fetal heart undergoes extensive maturational changes. Here, we describe a method for the chronic implantation of radiotelemetry devices into late gestation ovine fetuses to characterize parameters of the fECG following surgery, throughout late gestation, and in the perinatal period. We found no significant changes in mean aortic pressure (MAP), heart rate (HR), or ECG in the 5 days following implantation; however, HR decreased in the first 24 h following the end of surgery, with associated increases in RR, PR, and QRS intervals. Over the last 14 days of fetal life, fetal MAP significantly increased, and HR significantly decreased, as expected. MAP and HR increased as labor progressed. Although there were no significant changes over time in the ECG during late gestation, the duration of the PR interval initially decreased and then increased as birth approached. These results indicate that although critical maturational changes occur in the late gestation fetal myocardium, the mechanisms that control the cardiac conduction are relatively mature in late gestation. The study demonstrates that radiotelemetry can be successfully used to assess fetal cardiac function, in particular conduction, through the process of labor and delivery, and may therefore be a useful tool for study of peripartum cardiac events.

Climacteric fruit such as peaches are stored in cold chambers after harvest and usually are maintained there until the desired ripening is reached to direct these fruit to market. Producers, food industries and or traders have difficulties in defining the period when fruit are at the highest level of quality desired by consumers in terms of the physical-chemical parameters (hardness –H–, soluble solids content –SSC–, and acidity –Ac–). The evolution of peach quality in terms of these parameters depends directly on storage temperature –T– and relative humidity –RH–, as well on the storage duration –t–. This paper describes an Artificial Intelligence (AI) Decision Support System (DSS) designed to predict the evolution of the quality of peaches, namely the storage time required before commercialization as well as the late commercialization time. The peaches quality is stated in terms of the values of SSC, H and Ac that consumers most like for the storage T and RH. An Artificial neuronal network (ANN) is proposed to provide this prediction. The training and validation of the ANN were conducted with experimental data acquired in three different farmers’ cold storage facilities. A user interface was developed to provide an expedited and simple prediction of the marketable time of peaches, considering the storage temperature, relative humidity, and initial physical and chemical parameters. This AI DSS may help the vegetable sector (logistics and retailers), especially smaller neighborhood grocery stores, define the marketable period of fruit. It will contribute with advantages and benefits for all parties—producers, traders, retailers, and consumers—by being able to provide fruit at the highest quality and reducing waste in the process. In this sense, the ANN DSS proposed in this study contributes to new AI-based solutions for smart cities.

Single-sided deafness (SSD) induces cortical neural plastic changes according to duration of deafness. However, it is still unclear how the auditory cortical changes accompany the subcortical neural changes. The present study aimed to find the neural plastic changes in the cortical and subcortical auditory system following adult-onset single-sided deafness (SSD) using Mn-enhanced magnetic resonance imaging (MEMRI). B57BL/6 mice (postnatal 8-week-old) were divided into three groups: the SSD-4-week group (postnatal 12-week-old, n = 11), the SSD-8-week group (postnatal 16-week-old, n = 11), and a normal-hearing control group (postnatal 8-week-old, n = 9). The left cochlea was ablated in the SSD groups. White Gaussian noise was delivered for 24 h before MEMRI acquisition. T1-weighted MRI data were analyzed from the cochlear nucleus (CN), superior olivary complex (SOC), lateral lemniscus (LL), inferior colliculus (IC), medial geniculate body (MG), and auditory cortex (AC). The differences in relative Mn2+-enhanced signal intensities (Mn2+SI) and laterality were analyzed between the groups. Four weeks after the SSD procedure, the ipsilateral side of the SSD showed significantly lower Mn2+SI in the CN than the control group. On the other hand, the contralateral side of the SSD demonstrated significantly lower Mn2+SI in the SOC, LL, and IC. These decreased Mn2+SI values were partially recovered at 8 weeks after the SSD procedure. The interaural Mn2+SI differences representing the interaural dominance were highest in CN and then became less prominently higher in the auditory neural system. The SSD-8-week group still showed interaural differences in the CN, LL, and IC. In contrast, the MG and AC did not show any significant intergroup or interaural differences in Mn2+SI. In conclusion, subcortical auditory neural activities were decreased after SSD, and the interaural differences were diluted in the higher auditory nervous system. These findings were attenuated with time. Subcortical auditory neural changes after SSD may contribute to the change in tinnitus severity and the outcomes of cochlear implantation in SSD patients.

Background: Seizures represent the most distinctive signal of neurological disease in the newborn period and these convulsive phenomena are the most frequent of the overt manifestation of neonatal neurological disorders. Recognition and classification of seizures remain problematic; particularly when pediatricians rely only on clinical criteria. The objective of this study was to study the incidence of pediatrics (0-12 years) seizures. To study the etiology and pattern of seizures.Methods: 326 Subjects who had seizures were included in the study. Relevant history was ascertained from a patient’s parents or a reliable relative or attendant, medical records and the referring physicians note, specifically from mother in case of neonatal seizures i.e. age at onset of seizures, seizure activity with special emphasis on occurrence of 1st seizures, duration of seizures, number and type of seizures, associated autonomic changes, medications required to control seizures, response time to medications, and possible causes for determination of etiology. A detailed antenatal, natal and postnatal history was taken.Results: Out of 326 study subjects 117 (35.89%) were in neonatal age group, of which 75 (64.10%) and 42 (35.90%) were male and female respectively and 209 (64.11%) were beyond neonatal age, out of which 125 (59.8%) were male and 84 (40.2%) female. out of 117 neonatal seizures, 75 (64.10%) neonates were male and 42 (35.90%) were female. Male: Female ratio was 1.79:1. The seizures were common in male neonates. Subtle seizures were the commonest type of seizures observed both in term and preterm neonates.Conclusions: The various types of seizure were compared with the preterm and term neonates and it was found statistically significant (X2 = 5.06 d.f. = 4, p<0.05). The various causes of seizure were compared with the preterm and term neonates and it was found statistically significant (X2= 17.42 d.f. = 6 p<0.05).

Abstract Abstract 3205 Poster Board III-142 Telomeres in peripheral blood cells from patients with aplastic anemia (AA) are shorter than those from normal individuals. One possible explanation is that telomere shortening reflects the extent and duration of damage to hematopoietic stem cells and the number of compensatory stem cell divisions. Patients with such stressed hematopoiesis probably do not respond to immunosuppressive therapy (IST). Cryptic forms of dyskeratosis congenita (DC) have been recognized in patients with AA who do not have physical abnormalities, but who harbor the gene mutation associated with telomere maintenance. To identify such patients is important because those who have these mutations might respond poorly to IST. The present study evaluates the usefulness of screening telomere length in peripheral blood lymphocytes from patients at the time of diagnosis with AA by flow-fluorescence in situ hybridization (flow-FISH) using Telomere PNA kits (Dako Cytomation, Glostrup, Denmark). After gating diploid cells based on propidium iodine staining, lymphocytes were isolated according to size and granularity. Relative telomere length (RTL) was calculated as the ratio between the telomere signal of each sample and the telomere signal of the control cell line. Because telomeres shorten with age, we obtained age-adjusted measurements for comparison. We used flow-FISH to measure the length of telomeres in peripheral blood lymphocytes from five and two patients with classical and cryptic DC who had the TERT mutation, respectively, to determine whether these two forms of DC can be screened. Significant telomere shortening was detected in all seven patients compared with age-matched normal individuals. To determine the association between telomere length and response to IST, we compared telomere lengths in peripheral blood lymphocytes from 61 normal controls and 27 patients with AA (very severe, severe and non-severe, n = 9 each) at diagnosis who received IST with antithymocyte globulin (ATG) and cyclosporine. The median age of the patients was 9.0 years (range, 1.5 to 14.8). The causes of AA were unknown etiology in 25 patients and hepatitis in 2. In total, 17 of the 27 patients (63%) responded to IST at 6 months after administration of ATG. Age-adjusted delta RTLs did not significantly differ between normal controls and responders (p = 0.181), but those in non-responders were significantly lower than those in normal individuals (p = 0.000). Our findings suggest that screening telomere length in patients with AA at diagnosis is useful for detecting cryptic DC and for predicting responses to IST. Disclosures No relevant conflicts of interest to declare.

Over the last 2 decades, four major therapeutic approaches have drastically changed the prognosis in chronic myelogenous leukemia (CML): 1) allogeneic stem cell transplant (SCT); 2) interferon alpha (IFN-α) based regimens; 3) donor lymphocyte infusions (DLI); and 4) and the revolutionary BCR-ABL tyrosine kinase inhibitors such as STI571 (signal transduction inhibitor 571). Each modality has exploited and targeted different aspects of CML biology, and is associated with different risk-benefit ratios. In Section I of this review, Dr. Melo reviews the molecular pathophysiology of CML and potential new targets for therapy including anti-sense strategies to disrupt the BCR-ABL gene and inhibition of the BCR-ABL tyrosine kinase activity. In Section II, Dr. Tura, addresses important questions in the use of IFN-α for the treatment of CML, including the mechanism of action and the development of resistance, the optimal dose and duration of therapy and the prediction of response based on clinical features. An approach to the choice of therapy based on the predicted mortality is presented. In Section III Dr. Giralt presents an update on the results of unrelated donor transplantion, donor lymphocyte infusions (DLI) and non-ablative stem cell transplantation (NST) in CML. The roles of CD8-depletion, dose escalation and the transduction of suicide genes in treatment with DLI are addressed. Early results of NST in CML show that it is feasible and can result in long-term disease control. In Section IV Drs. Kantarjian and Talpaz review the results of IFN-α plus low-dose cytosine arabinoside and other promising modalities for CML including homoharringtonine, decitabine, and polyethylene glycol-interferon. In Section V they present an update on the recent experience with STI571. Objective but transient responses have been seen in 40% to 50% of patients in CML blastic phase. In accelerated phase, the response rate with STI571 exceeds 70%, and these responses are durable. In chronic phase CML, STI571 at 300 mg daily in patients who failed IFN-α produces a complete hematologic response (CHR) in over 90% of patients. Early results suggest cytogenetic response rates of approximately 50%, which may be major in approximately 30%. The maturing results with STI571 may soon change current recommendations regarding the relative roles of established modalities such as allogeneic SCT and IFN-α. Important questions include 1) whether STI571 therapy alone may be sufficient to induce long-term survival and event-free survival in CML, or whether it needs to be combined simultaneously or sequentially with IFN-α and cytosine arabinoside; and 2) what should the indications for frontline allogeneic SCT be in relation to STI571 therapy.

Abstract Over the last 2 decades, four major therapeutic approaches have drastically changed the prognosis in chronic myelogenous leukemia (CML): 1) allogeneic stem cell transplant (SCT); 2) interferon alpha (IFN-α) based regimens; 3) donor lymphocyte infusions (DLI); and 4) and the revolutionary BCR-ABL tyrosine kinase inhibitors such as STI571 (signal transduction inhibitor 571). Each modality has exploited and targeted different aspects of CML biology, and is associated with different risk-benefit ratios. In Section I of this review, Dr. Melo reviews the molecular pathophysiology of CML and potential new targets for therapy including anti-sense strategies to disrupt the BCR-ABL gene and inhibition of the BCR-ABL tyrosine kinase activity. In Section II, Dr. Tura, addresses important questions in the use of IFN-α for the treatment of CML, including the mechanism of action and the development of resistance, the optimal dose and duration of therapy and the prediction of response based on clinical features. An approach to the choice of therapy based on the predicted mortality is presented. In Section III Dr. Giralt presents an update on the results of unrelated donor transplantion, donor lymphocyte infusions (DLI) and non-ablative stem cell transplantation (NST) in CML. The roles of CD8-depletion, dose escalation and the transduction of suicide genes in treatment with DLI are addressed. Early results of NST in CML show that it is feasible and can result in long-term disease control. In Section IV Drs. Kantarjian and Talpaz review the results of IFN-α plus low-dose cytosine arabinoside and other promising modalities for CML including homoharringtonine, decitabine, and polyethylene glycol-interferon. In Section V they present an update on the recent experience with STI571. Objective but transient responses have been seen in 40% to 50% of patients in CML blastic phase. In accelerated phase, the response rate with STI571 exceeds 70%, and these responses are durable. In chronic phase CML, STI571 at 300 mg daily in patients who failed IFN-α produces a complete hematologic response (CHR) in over 90% of patients. Early results suggest cytogenetic response rates of approximately 50%, which may be major in approximately 30%. The maturing results with STI571 may soon change current recommendations regarding the relative roles of established modalities such as allogeneic SCT and IFN-α. Important questions include 1) whether STI571 therapy alone may be sufficient to induce long-term survival and event-free survival in CML, or whether it needs to be combined simultaneously or sequentially with IFN-α and cytosine arabinoside; and 2) what should the indications for frontline allogeneic SCT be in relation to STI571 therapy.

Background:Systemic sclerosis (SSc) is a rare connective tissue disease with abnormalities in vasculopathy, immune dysregulation and fibrosis resulting in skin and internal organ damages. Severity of skin involvement is known to correlate with organ-related mortality in particular pulmonary involvement. Variables skin assessment tools are available, modified Rodnan Skin Score (mRSS) is currently best validated and used widely. The immediate action of finding an ideal, clinically convenient objective methods is crucial to better clinicians‘ care for SSc patents.Objectives:Explore the potential of commercially available handheld, non-invasive devices for SSc skin analysis.Methods:1.Measure skin surface Adenosine Triphosphate (ATP) level with handheld ATP bioluminator (SystemSURE Plus, Hygiena) over the forearm of SSc(n= 51) and controls (n=50) 60seconds after sterilization to eliminate extrinsic factors. The bioluminometer expresses ATP test results in Relative Light Units (RLU) that is directly proportional to the amount of ATP on the test sample (Unit conversion: 1RLU = 1fM).2.In-vivo Raman Spectra measurement of SSc skin comparing with matched healthy controls on proximal phalangeal, area between 2nd and 3rd metacarpal and forearm. Our measurments include laser power of 250mw, excitation length of 785nm and spectral range from 500 to 2800cm-1.Measurements were analysed with patients’ phenotypes and clinical characteristics.Results:Flow cytometry showed increase expression of P2X7 (purinergic) receptor and CD206 in M2-Macrophage in SSc compare to controls [(724.4 vs 472.9, 776.1 vs 632.2)]. CD206 expression positively correlated with P2X7 levels (p<0.001, r2=0.76) and mRSS (p<0.05, r2=0.26). In real life scenario, measurement of purinergic metabolites is laboratorial tedious. ATP bioluminator measurement reviewed significant higher skin surface ATP in SSc than controls (188fM ± 53 [95% CI = 84, 300] vs 44fM ± 6 [95% CI = 33, 56], p< 0.003). And the intensity is negatively correlate with duration of disease in SSc (r = - 0.25, p = 0.096).We obtain Raman spectra in SSc patient and control. Our study both groups have similar Raman curve when Raman Spectrometry were performed on skin surfaces. However, the relative intensity of each peaks of the curve were overtly flatter in SSc. This finding were similar for both Limited and Diffuse SSc in gross review of the graph representative. In addition to that, our analysis reviewed a peak at Raman shift of 2410 cm-1 that is characteristically present in forearm of a SSc but not in controls (Figure 1). Its significant yet to be determined.Conclusion:Both ATP bioluminator and Raman Spectrometry is widely available commercially which are widely used in industrial, agriculture and cosmetology and dermatology in particular for Raman Spectrometry. It is commonly for assessing physically property of skin, determine drug administration and diagnosis of variable skin condition in particular cancer diagnosis. The advantages of these tools in SSc skin analysis include:1.Non-invasive nature of skin analysis (compares to skin biopsy),2.Portable devices easily mobilized in clinic setting,3.Advanced technology allows molecular analysis of skin hence able to objectively classify grades of skin inflammation and determine drug efficacy4.Possible better accuracy compares to other methods (eg. Ultrasound) which are operators dependent,5.Widely available Raman signal database of different types of chemical compounds and expertise made the collection and analysis of date convenientOur study has provide preliminary outlook and idea of utilizing commercially available devices on skin analysis in SSc. Further study in larger cohort are to be considered.References:[1]Burnstock G, Knight GE, Greig AV. Purinergic signaling in healthy and diseased skin. The Journal of investigative dermatology. 2012;132(3 Pt 1):526-46.[2]Franzen L, Windbergs M. Applications of Raman spectroscopy in skin research. Advanced Drug Delivery Reviews.Volume 89.2015. Pages 91-104.Disclosure of Interests:None declared

BackgroundSUMOylation is a post-translational modification that serves as an important modulator of immune responses via its role in constraining the type I interferon (IFN-1) response. TAK-981 is a small molecule that inhibits SUMOylation and increases IFN-1-dependent innate immune responses with the potential to enhance adaptive immunity. Here, we report dose-escalation data from a TAK-981 Phase 1/2 clinical study (NCT03648372), the first clinical data for a SUMOylation inhibitor.MethodsAdults with advanced/metastatic solid tumors or relapsed/refractory lymphomas received TAK-981 IV twice-weekly (BIW; days 1, 4, 8, 11) or once-weekly (QW; days 1, 8) in 21-day cycles. Dose escalation was guided by a Bayesian Logistic Regression Model (BLRM) with overdose control, plus available pharmacokinetic/pharmacodynamic (PK/PD) data. Phase 1 objectives were to determine TAK-981 safety/tolerability and establish the recommended phase 2 dose (RP2D).ResultsSeventy-six patients received TAK-981 at 10 dose levels (3–40 mg BIW; 60–120 mg QW/BIW). Median age was 61 years (range, 38–79); 42 (55.3%) patients were female. Four dose-limiting toxicities were seen in 62 evaluable patients (transient grade 3 ALT/AST elevation, 60 mg BIW; grade 3 pneumonitis, 90 mg BIW; grade 3 stomatitis and grade 3 cognitive disturbance, 120 mg BIW). Per BLRM, 120 mg BIW was determined to be the maximum tolerated dose. At data cut-off, median treatment duration was 2 cycles (range, 1–12); 13 (17.1%) patients were ongoing. table 1 summarizes TAK-981 safety. The most common (≥20%) treatment-emergent adverse events (TEAEs) were fatigue (42.1%), nausea (39.5%), headache (31.6%), diarrhea (28.9%), pyrexia (27.6%), vomiting (23.7%), decreased appetite (22.4%). Common (≥5%) grade ≥3 TEAEs were hypokalemia (9.2%), anemia (7.9%), lymphocyte count decreased (6.6%), abdominal pain (5.3%). Grade 2 cytokine release syndrome was reported in 4 (5.2%) patients; symptoms resolved within 12–24 hours with supportive oxygen and/or IV fluids. One partial response was observed at 40 mg TAK-981 BIW in a patient with relapsed/refractory HER2-negative, hormone receptor-positive breast cancer. TAK-981 exhibited linear PK, with approximately dose-proportional exposure and a mean terminal half-life of 3.8–10.8 hours at ≥60 mg. Evidence of dose-dependent target engagement (figure 1), and PD (figures 2–4) in blood were observed. The single-agent TAK-981 RP2D was 90 mg BIW.Abstract 476 Table 1Summary of TAK-981 safety profileAbstract 476 Figure 1PD in patients receiving TAK-981 on the BIW schedule: target engagement.Blood samples were collected on Cycle 1 Day 1 pre-dose and at multiple timepoints after TAK-981 administration. Target engagement in T cells was detected by flow cytometry with an antibody recognizing the TAK-981-SUMO adduct formed during the inhibition of the SUMO-activating enzyme by TAK-981; Cycle 1 Day 1 signal increased at 1 hour post-end-of-infusion compared to the background level observed pre-dose.Abstract 476 Figure 2PD in patients receiving TAK-981 on the BIW schedule: SUMOylation.SUMOylation in T cells, detected by flow cytometry with an antibody recognizing SUMO2/3, decreased at 1 hour post-end-of-infusion on Cycle 1 Day 1 compared to pre-dose, indicating that fewer SUMO2/3 chains are formed when the SUMO-activating enzyme is inhibited.Abstract 476 Figure 3PD in patients receiving TAK-981 on the BIW schedule: upregulation of CXCL10 expression.Upregulation of mRNA levels of CXCL10, an IFN-I-regulated gene, in peripheral blood. Gene expression was measured using Nanostring nCounter at Cycle 1 Day 1 pre-dose and at several timepoints post-dose. Data for maximum increase at 8 or 24 hours, relative to pre-dose, is shown.Abstract 476 Figure 4PD in patients receiving TAK-981 on the BIW schedule: NK cell activation.NK cell activation in peripheral blood measured by flow cytometry. Percentage of CD69-positive NK cells at Cycle 1 Day 1 pre-dose and at 24 hours post-end-of-infusion is shown by patient for each dose.ConclusionsThe data generated in this study support continued TAK-981 development for treatment of solid tumors and lymphoma. The Phase 2 study expansion is ongoing in patients with advanced/metastatic non-small-cell lung, cervical, and colorectal cancer, and in relapsed/refractory non-Hodgkin lymphoma.Trial RegistrationClinical Trial identification: ClinicalTrials.gov. Identifier: NCT03648372Ethics ApprovalThe study was approved by the Institutional Review Board or Institutional Ethics Committee of all participating institutions

Abstract Introduction The standard primary endpoint in clinical trials of chronic lymphocytic leukemia (CLL) is progression-free survival (PFS). Given the increasingly long follow up required to detect differences in PFS between treatment arms in the era of more efficient therapeutics, valid surrogate endpoints are urgently needed to reduce clinical trial duration, thereby accelerating drug development, reducing costs and allowing patients (pts) earlier access to novel treatment options. Pts with CLL who achieve levels of minimal residual disease (MRD) of <1 clonal cell/10.000 leukocytes in peripheral blood (PB) as determined by multicolor flow cytometry or allele-specific oligonucleotide real-time quantitative polymerase chain reaction (ASO-RQ-PCR) at the end of initial treatment are considered MRD negative, and have been shown to experience significantly improved PFS. This analysis aimed to support the evaluation of MRD response at the end of treatment as a surrogate endpoint for PFS in CLL, based on a retrospective analysis of 3 multicenter, randomized, Phase 3 clinical trials. Methods MRD was prospectively assessed in PB of treatment-naive pts with CLL that participated in the German CLL Study Group CLL8, CLL10 and CLL11 multicenter, randomized, open-label, Phase 3 clinical trials, which included induction treatment followed by observation. The primary endpoint of each study was investigator-assessed PFS. MRD was quantified by 4-color flow cytometry in CLL8 and CLL10, and ASO RQ-PCR in CLL11. Both methods had a detection threshold of 1 CLL cell/10,000 leukocytes. Pts who had no MRD result but had disease progression or died shortly after 6 treatment cycles (within 90 [CLL8 and CLL10] or 56 [CLL11] days of last dose) were included and classed as MRD positive. A meta-regression model was developed to predict treatment effect on PFS using treatment effect on MRD. Log ratio was selected as the most reliable representation of MRD response based on the best model fit. To ensure no systemic bias with pt selection, demographic characteristics and efficacy results for the pt population used in the MRD analysis were compared with the respective intent-to-treat populations for each study. Results PB MRD levels at the end of treatment (CLL8 and CLL10, 75-195 days after last dose; CLL11, 56-190 days after last dose) were assessed in 393, 336, and 474 pts from CLL8, CLL10 and CLL11, respectively. PFS events occurred in 24% to 51% of pts assessed for MRD assigned to the experimental arm and in 34% to 67% assigned to active control treatment. Key efficacy data for the 3 trials are shown in Table 1. To fit a meta-regression model, each study was split into subgroups according to region (CLL8), country (CLL11) or randomly (CLL10). For each subgroup, the PFS hazard ratio (HR) was plotted against the ratio of MRD response rates (MRD negative rate in experimental arm to MRD negative rate in control arm, on a log-scale), and a regression line fitted to reflect the relationship between the two parameters (Figure 1). Circle size represents the weighting of each subgroup to the overall model; least variability in PFS HR have the largest circles. Clustering of circles by study reflects the overall treatment effect (for both MRD and PFS) in the studies. A statistically significant relationship between improved MRD response rates and reduction in the risk of disease progression or death was observed (for each unit increase in log of the ratio of MRD response rates, the log of PFS HR decreases by -0.299; 95% CI, -0.441 to -0.157; p=0.0004). Predictions based on this meta-regression model suggest that risk of progression or death decreases as the ratio of MRD response rates (MRD relative risk: MRD-negative rate in experimental arm/MRD-negative rate in control arm) increases (Table 2); i.e. a larger difference in MRD-response rates leads to lower PFS HR. Conclusion A surrogate endpoint (MRD) should not only provide prognostic value for the specific clinical outcome (PFS), but also evidence that treatment effect on the surrogate endpoint (MRD) reliably predicts treatment effect on the clinical outcome (PFS). Results of the meta-regression model show a significant association between treatment effect on MRD and treatment effect on PFS with regard to chemoimmunotherapy. The findings also suggest that treatment effect on PFS can be predicted based on treatment effect on MRD response. This model supports the use of MRD as a surrogate for PFS in pts with CLL. Disclosures Dimier: Roche: Employment. Delmar:F. Hoffmann-La Roche, Ltd.: Employment, Equity Ownership. Ward:F. Hoffmann-La Roche Ltd: Employment. Morariu-Zamfir:F. Hoffmann-La Roche Ltd: Employment. Fingerle-Rowson:Roche: Employment, Equity Ownership. Fischer:Roche: Other: Travel Grants. Eichhorst:Mundipharma: Consultancy, Research Funding, Speakers Bureau; AbbVie: Consultancy; Roche: Consultancy, Research Funding, Speakers Bureau. Goede:Mundipharma: Honoraria; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; GSK: Honoraria; Bristol-Myers Squibb: Honoraria. van Dongen:InVivoScribe: Patents & Royalties: Licensing of IP and Patent on BIOMED-2-based methods for PCR-based Clonality Diagnostics. Royalty income for EuroClonality-BIOMED-2 Consortium.; DAKO: Patents & Royalties: Licensing of IP and Patent on Split-Signal FISH. Royalties for Dept. of Immunology, Erasmus MC, Rotterdam, NL; Cytognos: Patents & Royalties: Licensing of Patent on detection of IgE+ B-cells in allergic diseases. Royalties for Dept. of Immunology, Erasmus MC, Rotterdam, NL; Cytognos: Patents & Royalties: Licensing of IP on Infinicyt software, Patents on EuroFlow-based flowcytometric Diagnosis and Classification of hematological malignancies, Patents on MRD diagnostics, and Patents on PID diagnostics. Royalty income for EuroFlow Consortium.; BD Biosciences: Other: Educational Lectures and Educational Workshops (+ related travelling costs). Laboratory Services in the field of technical validation of EuroFlow-OneFlow antibody tubes in dried format. Provided by the Laboratory of Medical Immunology, Erasums MC, Patents & Royalties; Roche: Consultancy, Other: Laboratory Services in the field of MRD diagnostics, provided by the Laboratory of Medical Immunology, Dept. of Immunology, Erasmus MC, Rotterdam, NL; Immunostep: Patents & Royalties: Licensing of IP and Patents on immunobead-based dection of fusion proteins in acute leukemias and other tumors. Royalties for Dept. of Immunology, Erasmus MC and for EuroFlow Consortium. Ritgen:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Böttcher:Celgene: Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Beckton Dickinson: Honoraria. Langerak:InVivoScribe: Patents & Royalties: Licensing of IP and Patent on BIOMED-2-based methods for PCR-based Clonality Diagnostics. ; DAKO: Patents & Royalties: Licensing of IP and Patent on Split-Signal FISH. Royalties for Dept. of Immunology, Erasmus MC, Rotterdam, NL; Roche: Other: Lab services in the field of MRD diagnostics provided by Dept of Immunology, Erasmus MC (Rotterdam). Hallek:Janssen: Honoraria, Other: Speakers Bureau and/or Advisory Board, Research Funding; Gilead: Honoraria, Other: Speakers Bureau and/or Advisory Board, Research Funding; Roche: Honoraria, Other: Speakers Bureau and/or Advisory Board, Research Funding; Celgene: Honoraria, Other: Speakers Bureau and/or Advisory Board, Research Funding; Pharmacyclics: Honoraria, Other: Speakers Bureau and/or Advisory Board, Research Funding; Mundipharma: Honoraria, Other: Speakers Bureau and/or Advisory Board, Research Funding; Boehringher Ingelheim: Honoraria, Other: Speakers Bureau and/or Advisory Board; AbbVie: Honoraria, Other: Speakers Bureau and/or Advisory Board, Research Funding.

Climate change induced sea-level rise (SLR) is on its increase globally. Regionally the lowlands of China, Vietnam, Bangladesh, and islands of the Malaysian, Indonesian and Philippine archipelagos are among the world’s most threatened regions. Sea-level rise has major impacts on the ecosystems and society. It threatens coastal populations, economic activities, and fragile ecosystems as mangroves, coastal salt-marches and wetlands. This paper provides a summary of the current state of knowledge of sea level-rise and its effects on both human and natural ecosystems. The focus is on coastal urban areas and low lying deltas in South-East Asia and Vietnam, as one of the most threatened areas in the world. About 3 mm per year reflects the growing consensus on the average SLR worldwide. The trend speeds up during recent decades. The figures are subject to local, temporal and methodological variation. In Vietnam the average values of 3.3 mm per year during the 1993-2014 period are above the worldwide average. Although a basic conceptual understanding exists that the increasing global frequency of the strongest tropical cyclones is related with the increasing temperature and SLR, this relationship is insufficiently understood. Moreover the precise, complex environmental, economic, social, and health impacts are currently unclear. SLR, storms and changing precipitation patterns increase flood risks, in particular in urban areas. Part of the current scientific debate is on how urban agglomeration can be made more resilient to flood risks. Where originally mainly technical interventions dominated this discussion, it becomes increasingly clear that proactive special planning, flood defense, flood risk mitigation, flood preparation, and flood recovery are important, but costly instruments. Next to the main focus on SLR and its effects on resilience, the paper reviews main SLR associated impacts: Floods and inundation, salinization, shoreline change, and effects on mangroves and wetlands. The hazards of SLR related floods increase fastest in urban areas. This is related with both the increasing surface major cities are expected to occupy during the decades to come and the increasing coastal population. In particular Asia and its megacities in the southern part of the continent are increasingly at risk. The discussion points to complexity, inter-disciplinarity, and the related uncertainty, as core characteristics. An integrated combination of mitigation, adaptation and resilience measures is currently considered as the most indicated way to resist SLR today and in the near future.References Aerts J.C.J.H., Hassan A., Savenije H.H.G., Khan M.F., 2000. Using GIS tools and rapid assessment techniques for determining salt intrusion: Stream a river basin management instrument. 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One of the ways to design more effective signal control strategies is to leverage and synthesize connected vehicle generated (CVG) information to identify traffic states for the controller to operate in a predictive, yet vehicle-actuated manner. The contribution of this paper is twofold: (1) it presents a framework for an advanced, online, signal control logic in a connected environment that utilizes information from connected vehicles (CVs) to augment high-resolution controller and/or sensor data, and (2) it applies the trajectory analytics to compare the performance of the new controller schemes with CVG data and functionalities relative to conventional, vehicle-actuated, control. The framework puts forward a predictive control logic that schedules phases in an acyclic manner over a variable planning horizon. Phase duration is continually evaluated in response to updated requests for service distributed among equipped vehicles and associated performance indicators. Within the same connected control setup, two measures of effectiveness of a decision were compared to determine the upper bound on the potential effectiveness of a more responsive control strategy. Finally, trajectory analytics was used to evaluate the effectiveness of the CV technology-based control scheme against the conventional one. The findings indicate that both control system performance assessment and optimization objectives should change with access to CVG data. Unlike current state of the practice controllers, the developed method is able to handle high and low demand states equally well. The designed connected controller is shown to be robust in handling varying traffic conditions and demand levels.

Experimental dependences U(t) of the electric voltage taken from an induction magnetic head (MH) moving relative to a magnetic carrier (MH) are presented. The backgrounds of the edges of the MN, local defects of the MN, the background of the inhomogeneous magnetic field of the local source, the backgrounds of defects and structural inhomogeneities of the object, the etheric electromagnetic background, the background of the quality of the surface of the object and surface microscopic inhomogeneities of the material have been identified and investigated. The resonant backgrounds of self-excitation of the measuring system on the signals of the edges of the MN, defects of the MN, instrument and network pickups and interference, object defects, and etheric electromagnetic fields are revealed and investigated. Resonance peaks are the result of self-excitation of the measuring system, which includes the MG, and arise on the trailing edges of any signals of sufficient magnitude, the duration of the trailing edge of which is about a quarter of the period of natural oscillations of the measuring system. The amplitude and frequency spectra of the background signals of object defects, MI and noise and the analytical expressions describing them are determined. The results of the extraction of the useful signal from the complete signal recorded on the MN are shown. Investigations of the differential background of an electric signal allow, together with the previously developed methods of hysteresis interference, to control the properties of objects in an automatic mode with program control, which significantly increases the sensitivity and accuracy of control. To achieve this goal, it is recommended to set the parameters of the measurement system at the threshold of the onset of natural free oscillations in it.

In order to determine the technical condition of energetic objects with the objective of ensuring their operational reliability, durability and safety, systems of noise diagnostics, which are based on the analysis of acoustic diagnostic signals. A promising area of noise diagnostics are cumulant methods, based on cumulant analysis, which involves the use of cumulants and cumulant coefficients. In known literature no characteristics of detection of a signal within an interference-containing additive mixture with the use of a second-order cumulant (variance) can be found. That is why the objective of the paper is to study the use of cumulant method on the basis of point estimations of variance for a sample of momentary values for detection of an acoustic signal against the background of noise interference. The research was carried out by way of modeling the additive mixture of signal and interference using the MATLAB® software package. Interference is a model of a noise acoustic signal, which accompanies the operation of properly functional equipment. Signal is a model of an acoustic signal which is created with the occurrence of a malfunction. Signal and interference are independent random variables, so the property of additivity of cumulants was used – the variance of a mixture equals the sum of variances of signal and interference. The decision about the presence of a signal was made on the basis of testing two statistical hypotheses. The null hypothesis – the signal is absent, variance equals to the variance of the interference. The first hypothesis – the signal is present, variance equals to the variance of the mixture. Additional parameters: probability of a Type I error 0,01, probability of correct determination 0,99. The relative error of estimation determined the minimal sample size. These values allowed for the calculation of the threshold value, upon the exceeding of which by the variance estimation, the decision on the presence of signal is made. For each sample, assessments of variance were made. Experimental probability of correct determination is calculated as a total number of decisions taken regarding the presence of a signal, divided by the number of realizations, and corresponds to the value of the specified probability of correct determination. Its relative error was calculated in order to control the validity of the results. Also, kernel density estimation of the probability of the variance assessment for the case of a signal with normal distribution. As shown by the graphs, the assessments have a distribution that is close to normal. The conducted study proves that a variance -based cumulant method allows to detect a signal against the background of noise interference. The necessary sample size, which shows the number of the necessary momentary values, is given in the paper. That is to say that with the help of the frequency of an analogue digital converter the needed duration of the recording of a real for assessment of its variance can be obtained, and the decision on the presence or absence of a signal is to be made on the basis of the specified threshold values. The results of the study can be added to the known sample sizes and threshold values for the coefficients of asymmetry and excess with different distributions. Application of the described method requires additional testing on real acoustic signals and has the areas of use in systems of noise diagnostics.

AbstractPrecise monitoring of the brain after a stroke is essential for clinical decision making. Due to the non-invasive nature and high temporal resolution of electroencephalography (EEG), it is widely used to evaluate real-time cortical activity. In this study, we investigated the stroke-related EEG biomarkers and developed a predictive model for quantifying the structural brain damage in a focal cerebral ischaemic rat model. We enrolled 31 male Sprague–Dawley rats and randomly assigned them to mild stroke, moderate stroke, severe stroke, and control groups. We induced photothrombotic stroke targeting the right auditory cortex. We then acquired EEG signal responses to sound stimuli (frequency linearly increasing from 8 to 12 kHz with 750 ms duration). Power spectral analysis revealed a significant correlation of the relative powers of alpha, theta, delta, delta/alpha ratio, and (delta + theta)/(alpha + beta) ratio with the stroke lesion volume. The auditory evoked potential analysis revealed a significant association of amplitude and latency with stroke lesion volume. Finally, we developed a multiple regression model combining EEG predictors for quantifying the ischaemic lesion (R2 = 0.938, p value < 0.001). These findings demonstrate the potential application of EEG as a valid modality for monitoring the brain after a stroke.

Seizures represent signal of neurological disease in the newborn period and these convulsive phenomena are the most frequent of the overt manifestation of neonatal neurological disorders.. The objective of this study was to study the incidence of pediatrics (0-12 years) seizures. To study the etiology and pattern of seizures. Methods: 200 Subjects who had seizures were included in the study. Relevant history was ascertained from a patient’s parents or a reliable relative or attendant, medical records and the referring physicians note, specifically from mother in case of neonatal seizures i.e. age at onset of seizures, seizure activity with special emphasis on occurrence of 1st seizures, duration of seizures, number and type of seizures, associated autonomic changes, medications required to control seizures, response time to medications, and possible causes for determination of etiology. A detailed antenatal, natal and postnatal history was taken. Results: Out of 200 study subjects 35.89% were in neonatal age group, of which 64.10% and 35.90% were male and female respectively and 64.11%. out of neonatal seizures, 64.10% neonates were male and 35.90% were female. Male: Female ratio was 1.79:1. The seizures were common in male neonates. Subtle seizures were the commonest type of seizures observed both in term and preterm neonates. Conclusions: The various types of seizure were compared with the preterm and term neonates and it was found statistically significant

By analysing the time of a simple auditory-motor reaction with mono-presentation of an audio signal, the effect of the electromagnetic radiation of a mobile phone on the human auditory system is evaluated. Regularities in the frequency of occurrence of ipsi and contralateral effects in mobile users of different age groups are obtained. This study has no analogues in either Russian or foreign publications and is currently exclusive. The purpose was to study age-related features of the severity of ipsi and contralateral effects, depending on the mode of use of the mobile phone. To record the ipsi- and contralateral effects, we used the differences in the average values of a simple auditory-motor reaction between the left and right ears with mono-presentation of the sound signal of 573 respondents of different age groups. The obtained values were compared with the control group data for each age group (491 respondents). If the difference was greater than in the control group, the ipsilateral or contralateral effect was recorded. The severity of the effect was evaluated taking into account the lateral preferences of each participant in the experiments (to which ear the mobile phone is most often held) and the mode of use of the mobile phone. Statistical processing of the results was carried out using the non-parametric Mann-Whitney test and the method of descriptive statistics: prevalence indicator (Pr) (relative frequency of manifestation of a particular attribute in the sample). The comparison of the severity of ipsi and contralateral effects for different age groups allowed us to establish the following patterns. It was found that, in general, the manifestation of the contralateral effect decreases with age, and the ipsilateral effect increases. However, this change is not linear. It is shown that the features of the manifestation of the contralateral and ipsilateral effect for each age group depend both on the time of daily use of a mobile phone and on the total duration of use of a mobile phone. We believe that when studying multidimensional input data, an individual approach is necessary. The presented results confirm the negative effect of the radiation of mobile phones on the auditory system, primarily of our younger generation. Given the special vulnerability of children to physical environmental factors and the depth of penetration of EMR MT into the brain of a child, we believe that from a radiobiological point of view, there is already a need to develop a special SanPiN (sanitary rules and norms) for all available modern low-intensity sources of electromagnetic radiation, including Wi-Fi.

The ob protein, termed leptin, is produced by adipocytes and is thought to act as an afferent satiety signal regulating weight through suppressing appetite and stimulating energy expenditure in humans and/or rodents. Insulin has been found to be a potent stimulator of leptin expression in rodents. It is unclear at present whether this insulin action is a direct or an indirect effect. To investigate whether leptin concentrations in children and adolescents with type 1 diabetes (IDDM) were related to metabolic status, body weight, body mass index and insulin treatment, we have measured leptin concentrations in serum from 13 newly diagnosed IDDM patients before the beginning of insulin treatment (8 girls, 5 boys, aged 4.7-17.5 years) and in 134 patients with IDDM during treatment (64 girls, 70 boys, aged 2.6-20.1 years) using a specific radioimmunoassay. The data from patients with diabetes were compared with normative data that were derived from a large cohort of healthy children and adolescents. Serum from children with newly diagnosed diabetes had significantly lower levels of leptin (mean 1.28+/-1.60 ng/ml, range 0.14-6.13 ng/ml) compared with healthy children (n=710) (mean 2.2 ng/ml, range 0.26-14.4ng/ml) and compared with insulin-treated children and adolescents (mean 5.18+/-5.48 ng/ml, range 0.26-29.77 ng/ml) (P<0.0001) even after adjustment for gender and body mass index (BMI). Serum leptin levels in patients with IDDM were significantly correlated with BMI (r=0.42, P<0.0001). Multiple regression analysis showed that age and BMI were significantly correlated with leptin levels, while duration of diabetes, mean HbA1c levels, insulin dose and plasma glucose, triglyceride and cholesterol levels were not. Females had higher serum leptin concentrations than males even when adjusted for BMI (P<0.0001). Surprisingly and most importantly, leptin levels in insulin-treated young adult (Tanner stage 5) patients were significantly higher than values found in the healthy nondiabetic reference population when adjusted for sex, Tanner stage and BMI. These findings suggest that leptin levels in IDDM patients show a similar dependency on adipose tissue and age as in healthy, normal children. The data provide evidence that insulin may be of importance as a regulator of serum leptin levels in vivo not only in rodents but also in humans. It is hypothesized that the elevated BMI-adjusted leptin levels in adolescents with IDDM could indicate either that these patients may be oversubstituted by the intensified insulin therapy that they are receiving or that their body composition and body fat content may differ from that of healthy adolescents in the sense that they have a relative increase in fat mass.

Abstract Study question Does sodium tungstate treatment induce a change in endometrial cells’ capacity to implant trophoblasts? Summary answer Administration of sodium tungstate to endometrial cells increases trophoblast adhesion. What is known already Sodium tungstate (ST) has shown its capacity to modulate the activity of cytokines, such as leptin, an activator of an obligatory signalling cascade in the embryo-implantation process. STAT3, a signal transducer molecule critical for the embryo implantation process, is also known to be activated by ST. Still, ST’s effect on implantation using biological systems has never been studied. Embryo implantation process and endometrium roles are complicated to study in vivo due to a lack of animal models and appropriate techniques. In vitro techniques using immortalised cell lines allows a first approach to study early implantation stages, such as embryo adhesion. Study design, size, duration An in vitro study was carried out using a human endometrial carcinoma cell line (HEC–1-A) treated with sodium tungstate for 24 and 48h, and choriocarcinoma cell spheroids (JAr). Different times of treatment and concentrations were studied. Each experiment was performed in triplicate. Participants/materials, setting, methods Confluent endometrial HEC–1-A cultures were treated with ST at concentrations (0–150mM) and withaferin A (1mM), negative control for embryo adhesion. After the treatment period, HEC–1-A cultures were washed with ST-free culture medium to eliminate ST. Immediately, 15 JAr trophoblast spheroids were added to cultures and coincubated with gentle agitation for 30, 60 and 90 minutes. An inverted light microscope was used to count adhered and floating spheroids, and determine the trophoblast adherence ratio. Main results and the role of chance HEC–1-A cells treated with ST showed normal morphology and growth at all doses except 150mM. At the highest dose tested, the cells’ culture was still viable (negative blue trypan staining) and maintained morphology, but the adhesion to the plate surface was affected. Doses from 0.15 to 15mM were used to perform adhesion assays. HEC–1-A cells treated with ST for 24h showed an increased capacity to adhere JAr trophoblast spheroids. Adhesion rates reached significant differences at doses of 1.5 and 15mM after 60 and 90 minutes of coincubation. After 90 minutes, untreated cells reached 32.8% adhesion rate, while 1.5 and 15mM ST-treated cells reached 54.6% and 53.4% respectively (p &lt; 0.05 ST vs untreated). Thus, the increment of trophoblast adhesion rate induced by ST reached 66%. Lower adhesion rates were observed after 60 minutes of coincubation but were also significant with a relative increase of 49.1% at 1.5mM and 50.5% at 1.5mM when compared with untreated cells (p &lt; 0.05) Longer treatments (48h) showed similar trends to 24h-treatments, but with a lower extent of ST effect on HEC–1-A receptivity. Maximum adhesion rates were also observed at 90 minutes of coincubation and 1.5 and 15mM doses. The Mean adhesion rate increase was &gt;40% with both doses. Limitations, reasons for caution: The current study is the first approach to evaluate sodium tungstate effect on endometrium using an in vitro model. Future research using in vivo models should be performed to assess sodium tungstate effect on endometrium receptivity and its potential as a fertility treatment. Wider implications of the findings: We conclude that the direct effect of sodium tungstate on endometrial cells increases embryo adhesion rate. These results open a new research line to a potential treatment in human reproduction management with sodium tungstate to solve the unmet need of inducing embryo implantation. Trial registration number Not applicable