The extent of tumor-infiltrating lymphocytes (TILs), along with immunomodulatory ligands, tumor-mutational burden and other biomarkers, has been demonstrated to be a marker of response to ...immune-checkpoint therapy in several cancers. Pathologists have therefore started to devise standardized visual approaches to quantify TILs for therapy prediction. However, despite successful standardization efforts visual TIL estimation is slow, with limited precision and lacks the ability to evaluate more complex properties such as TIL distribution patterns. Therefore, computational image analysis approaches are needed to provide standardized and efficient TIL quantification. Here, we discuss different automated TIL scoring approaches ranging from classical image segmentation, where cell boundaries are identified and the resulting objects classified according to shape properties, to machine learning-based approaches that directly classify cells without segmentation but rely on large amounts of training data. In contrast to conventional machine learning (ML) approaches that are often criticized for their "black-box" characteristics, we also discuss explainable machine learning. Such approaches render ML results interpretable and explain the computational decision-making process through high-resolution heatmaps that highlight TILs and cancer cells and therefore allow for quantification and plausibility checks in biomedical research and diagnostics.
Sample preparation for high-throughput sequencing (HTS) includes treatment with various laboratory components, potentially carrying viral nucleic acids, the extent of which has not been thoroughly ...investigated. Our aim was to systematically examine a diverse repertoire of laboratory components used to prepare samples for HTS in order to identify contaminating viral sequences.
A total of 322 samples of mainly human origin were analysed using eight protocols, applying a wide variety of laboratory components. Several samples (60% of human specimens) were processed using different protocols. In total, 712 sequencing libraries were investigated for viral sequence contamination.
Among sequences showing similarity to viruses, 493 were significantly associated with the use of laboratory components. Each of these viral sequences had sporadic appearance, only being identified in a subset of the samples treated with the linked laboratory component, and some were not identified in the non-template control samples. Remarkably, more than 65% of all viral sequences identified were within viral clusters linked to the use of laboratory components.
We show that high prevalence of contaminating viral sequences can be expected in HTS-based virome data and provide an extensive list of novel contaminating viral sequences that can be used for evaluation of viral findings in future virome and metagenome studies. Moreover, we show that detection can be problematic due to stochastic appearance and limited non-template controls. Although the exact origin of these viral sequences requires further research, our results support laboratory-component-linked viral sequence contamination of both biological and synthetic origin.
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Abstract
Understanding the distribution and abundance of heat tolerant corals across seascapes is imperative for predicting responses to climate change and to support novel management actions. ...Thermal tolerance is variable in corals and intrinsic and extrinsic drivers of tolerance are not well understood. Traditional experimental evaluations of coral heat and bleaching tolerance typically involve ramp-and-hold experiments run across days to weeks within aquarium facilities with limits to colony replication. Field-based acute heat stress assays have emerged as an alternative experimental approach to rapidly quantify heat tolerance in many samples yet the role of key methodological considerations on the stress response measured remains unresolved. Here, we quantify the effects of coral fragment size, sampling time point, and physiological measures on the acute heat stress response in adult corals. The effect of fragment size differed between species (
Acropora tenuis
and
Pocillopora damicornis
). Most physiological parameters measured here declined over time (tissue colour, chlorophyll-
a
and protein content) from the onset of heating, with the exception of maximum photosynthetic efficiency (
F
v
/
F
m
) which was surprisingly stable over this time scale. Based on our experiments, we identified photosynthetic efficiency, tissue colour change, and host-specific assays such as catalase activity as key physiological measures for rapid quantification of thermal tolerance. We recommend that future applications of acute heat stress assays include larger fragments (> 9 cm
2
) where possible and sample between 10 and 24 h after the end of heat stress. A validated high-throughput experimental approach combined with cost-effective genomic and physiological measurements underpins the development of markers and maps of heat tolerance across seascapes and ocean warming scenarios.
The differentially rotating outer layers of stars are thought to play a role in driving their magnetic activity, but the underlying mechanisms that generate and sustain differential rotation are ...poorly understood. We report the measurement using asteroseismology of latitudinal differential rotation in the convection zones of 40 Sun-like stars. For the most significant detections, the stars' equators rotate approximately twice as fast as their midlatitudes. The latitudinal shear inferred from asteroseismology is much larger than predictions from numerical simulations.
Lateral tower vibrations of offshore wind turbines are normally lightly damped, and large amplitude vibrations induced by wind and wave loads in this direction may significantly shorten the fatigue ...life of the tower. This paper proposes the modeling and control of lateral tower vibrations in offshore wind turbines using active generator torque. To implement the active control algorithm, both the mechanical and power electronic aspects have been taken into consideration. A 13-degrees-of-freedom aeroelastic wind turbine model with generator and pitch controllers is derived using the Euler-Lagrangian approach. The model displays important features of wind turbines, such as mixed moving frame and fixed frame-defined degrees-of-freedom, couplings of the tower-blade-drivetrain vibrations, as well as aerodynamic damping present in different modes of motions. The load transfer mechanisms from the drivetrain and the generator to the nacelle are derived, and the interaction between the generator torque and the lateral tower vibration are presented in a generalized manner. A three-dimensional rotational sampled turbulence field is generated and applied to the rotor, and the tower is excited by a first order wave load in the lateral direction. Next, a simple active control algorithm is proposed based on active generator torques with feedback from the measured lateral tower vibrations. A full-scale power converter configuration with a cascaded loop control structure is also introduced to produce the feedback control torque in real time. Numerical simulations have been carried out using data calibrated to the referential 5-MW NREL (National Renewable Energy Laboratory) offshore wind turbine. Cases of drivetrains with a gearbox and direct drive to the generator are considered using the same time series for the wave and turbulence loadings. Results show that by using active generator torque control, lateral tower vibrations can be significantly mitigated for both gear-driven and direct-driven wind turbines, with modest influence on the smoothness of the power output from the generator.
New data from the years 2012 to 2015 from the Danish National Fungemia Surveillance are reported, and epidemiological trends are investigated in a 12-year perspective (2004 to 2015). During 2012 to ...2015, 1,900 of 1,939 (98%) fungal bloodstream isolates were included. The average incidence was 8.4/100,000 inhabitants, and this appears to represent a stabilizing trend after the increase to 10.1/100,000 in 2011. The incidence was higher in males than females (10.0 versus 6.8) and in patients above 50 years, and those changes were mainly driven by an increasing incidence among 80-to-89-year-old males (65.3/100,000 in 2014 to 2015). The proportion of
isolates decreased from 2004 to 2015 (64.4% to 42.4%) in parallel with a doubling of the proportion of
isolates (16.5% to 34.6%,
< 0.0001).
was more common among females (34.0% versus 30.4% in males). Following an increase in 2004 to 2011, the annual drug use stabilized during the last 2 to 3 years of that time period but remained higher than in other Nordic countries. This was particularly true for the fluconazole and itraconazole use in the primary health care sector, which exceeded the combined national levels of use of these compounds in each of the other Nordic countries. Fluconazole susceptibility decreased (68.5%, 65.2%, and 60.6% in 2004 to 2007, 2008 to 2011, and 2012 to 2015, respectively,
< 0.0001), and echinocandin resistance emerged in
(0%, 0.6%, and 1.7%, respectively,
< 0.001). Amphotericin B susceptibility remained high (98.7%). Among 16 (2.7%) echinocandin-resistant
isolates (2012 to 2015), 13 harbored FKS mutations and 5 (31%) were multidrug resistant. The epidemiological changes and the increased incidence of intrinsic and acquired resistance emphasize the importance of continued surveillance and of strengthened focus on antifungal stewardship.
The present paper presents the real‐time hybrid simulation (RTHS) technique for multimegawatt wind turbine (WT) with various types of full‐scale tuned liquid dampers (TLDs). As an evolvement of the ...pseudodynamic testing technique, the RTHS is executed in real time, thus allowing accurate investigation of the interaction between the aeroelastic WT system and the rate‐dependent nonlinear TLD device. As the numerical substructure, the WT is simulated in the computer using a 13‐degree‐of‐freedom (13‐DOF) aeroelastic model. As the physical substructure, the full‐scale TLDs are manufactured and physically tested. They are synchronized with each other by real‐time controllers. Taking advantage of RTHS technique, 2‐ and 3‐MW WTs have both been simulated under various turbulent wind conditions. TLDs with different configurations have been extensively investigated, eg, various tuning ratios by varying the water level, TLD without and with damping screens (various mesh sizes of the screen considered), and TLD with flat and sloped bottoms. It is shown that a well‐designed TLD is very effective in damping lateral tower vibrations of WTs. Furthermore, RTHS results and results from a proposed theoretical model are compared. This study gives comprehensive guidelines for employing various types of TLDs in large WTs and indicates huge potentials of applying RTHS technique in the area of wind energy.
Edgewise vibrations with low aerodynamic damping are of particular concern in modern multi-megawatt wind turbines, as large amplitude cyclic oscillations may significantly shorten the life-time of ...wind turbine components, and even lead to structural damages or failures. In this paper, a new blade design with active controllers is proposed for controlling edgewise vibrations. The control is based on a pair of actuators/active tendons mounted inside each blade, allowing a variable control force to be applied in the edgewise direction. The control forces are appropriately manipulated according to a prescribed control law. A mathematical model of the wind turbine equipped with active controllers has been formulated using an Euler–Lagrangian approach. The model describes the dynamics of edgewise vibrations considering the aerodynamic properties of the blade, variable mass and stiffness per unit length and taking into account the effect of centrifugal stiffening, gravity and the interaction between the blades and the tower. Aerodynamic loads corresponding to a combination of steady wind including the wind shear and the effect of turbulence are computed by applying the modified Blade Element Momentum (BEM) theory. Multi-Blade Coordinate (MBC) transformation is applied to an edgewise reduced order model, leading to a linear time-invariant (LTI) representation of the dynamic model. The LTI description obtained is used for the design of the active control algorithm. Linear Quadratic (LQ) regulator designed for the MBC transformed system is compared with the control synthesis performed directly on an assumed nominal representation of the time-varying system. The LQ regulator is also compared against vibration control performance using Direct Velocity Feedback (DVF). Numerical simulations have been carried out using data from a 5-MW three-bladed Horizontal-Axis Wind Turbine (HAWT) model in order to study the effectiveness of the proposed active controlled blade design in reducing edgewise vibrations. Results show that the use of the proposed control scheme significantly improves the response of the blade and promising performances can be achieved. Furthermore, under the conditions considered in this study quantitative comparisons of the LQ-based control strategies reveal that there is a marginal improvement in the performances obtained by applying the MBC transformation on the time-varying edgewise vibration model of the wind turbine.
► Active controller design to suppress edgewise vibrations in wind turbine blades proposed. ► Control is based on actuators/active tendons mounted inside blades. ► Multi-modal model includes centrifugal stiffening, gravity effects and aerodynamic loading. ► Multi-blade coordinate transformation applied to the time-varying edgewise model. ► Linear quadratic regulator designed and different control strategies compared.
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