CAFA-evaluator: a Python tool for benchmarking ontological classification methods.

We present CAFA-evaluator, a powerful Python program designed to evaluate the performance of prediction methods on targets with hierarchical concept dependencies. It generalizes multi-label evaluation to modern ontologies where the prediction targets are drawn from a directed acyclic graph and achieves high efficiency by leveraging matrix computation and topological sorting. The program requirements include a small number of standard Python libraries, making CAFA-evaluator easy to maintain. The code replicates the Critical Assessment of protein Function Annotation (CAFA) benchmarking, which evaluates predictions of the consistent subgraphs in Gene Ontology. Owing to its reliability and accuracy, the organizers have selected CAFA-evaluator as the official CAFA evaluation software. Availability and implementation: https://pypi.org/project/cafaeval.

Learning from the unknown: exploring the range of bacterial functionality.

Determining the repertoire of a microbe's molecular functions is a central question in microbial biology. Modern techniques achieve this goal by comparing microbial genetic material against reference databases of functionally annotated genes/proteins or known taxonomic markers such as 16S rRNA. Here, we describe a novel approach to exploring bacterial functional repertoires without reference databases. Our Fusion scheme establishes functional relationships between bacteria and assigns organisms to Fusion-taxa that differ from otherwise defined taxonomic clades. Three key findings of our work stand out. First, bacterial functional comparisons outperform marker genes in assigning taxonomic clades. Fusion profiles are also better for this task than other functional annotation schemes. Second, Fusion-taxa are robust to addition of novel organisms and are, arguably, able to capture the environment-driven bacterial diversity. Finally, our alignment-free nucleic acid-based Siamese Neural Network model, created using Fusion functions, enables finding shared functionality of very distant, possibly structurally different, microbial homologs. Our work can thus help annotate functional repertoires of bacterial organisms and further guide our understanding of microbial communities.

An Approach to Identifying and Quantifying Bias in Biomedical Data.

Data biases are a known impediment to the development of trustworthy machine learning models and their application to many biomedical problems. When biased data is suspected, the assumption that the labeled data is representative of the population must be relaxed and methods that exploit a typically representative unlabeled data must be developed. To mitigate the adverse effects of unrepresentative data, we consider a binary semi-supervised setting and focus on identifying whether the labeled data is biased and to what extent. We assume that the class-conditional distributions were generated by a family of component distributions represented at different proportions in labeled and unlabeled data. We also assume that the training data can be transformed to and subsequently modeled by a nested mixture of multivariate Gaussian distributions. We then develop a multi-sample expectation-maximization algorithm that learns all individual and shared parameters of the model from the combined data. Using these parameters, we develop a statistical test for the presence of the general form of bias in labeled data and estimate the level of this bias by computing the distance between corresponding class-conditional distributions in labeled and unlabeled data. We first study the new methods on synthetic data to understand their behavior and then apply them to real-world biomedical data to provide evidence that the bias estimation procedure is both possible and effective.

Characterization and application of nonlinear plastic materials for post-CPA pulse compression.

We demonstrate the three-fold post-chirped-pulse-amplification (post-CPA) pulse compression of a high peak power laser pulse using allyl diglycol carbonate (CR39), which was selected as the optimal material for near-field self-phase modulation out of a set of various nonlinear plastic materials, each characterized with respect to its nonlinear refractive index and optical transmission. The investigated materials could be applied for further pulse compression at high peak powers, as well as for gain narrowing compensation within millijoule-class amplifiers. The post-CPA pulse compression technique was tested directly after the first CPA stage within the POLARIS laser system, with the compact setup containing a single 1 mm thick plastic sample and a chirped mirror pair, which enabled a substantial shortening of the compressed pulse duration and, hence, a significant increase in the laser peak power without any additional modifications to the existing CPA chain.

Efficient Laser-Driven Proton Acceleration from a Cryogenic Solid Hydrogen Target.

We report on the successful implementation and characterization of a cryogenic solid hydrogen target in experiments on high-power laser-driven proton acceleration. When irradiating a solid hydrogen filament of 10 µm diameter with 10-Terawatt laser pulses of 2.5 J energy, protons with kinetic energies in excess of 20 MeV exhibiting non-thermal features in their spectrum were observed. The protons were emitted into a large solid angle reaching a total conversion efficiency of several percent. Two-dimensional particle-in-cell simulations confirm our results indicating that the spectral modulations are caused by collisionless shocks launched from the surface of the the high-density filament into a low-density corona surrounding the target. The use of solid hydrogen targets may significantly improve the prospects of laser-accelerated proton pulses for future applications.

Controlling the Self-Injection Threshold in Laser Wakefield Accelerators.

Controlling the parameters of a laser plasma accelerated electron beam is a topic of intense research with a particular focus placed on controlling the injection phase of electrons into the accelerating structure from the background plasma. An essential prerequisite for high-quality beams is dark-current free acceleration (i.e., no electrons accelerated beyond those deliberately injected). We show that small-scale density ripples in the background plasma are sufficient to cause the uncontrolled (self-)injection of electrons. Such ripples can be as short as ∼50 µm and can therefore not be resolved by standard interferometry. Background free injection with substantially improved beam characteristics (divergence and pointing) is demonstrated in a gas cell designed for a controlled gas flow. The results are supported by an analytical theory as well as 3D particle in cell simulations.

Incorporation of CT-based measurements of trunk anatomy into subject-specific musculoskeletal models of the spine influences vertebral loading predictions.

We created subject-specific musculoskeletal models of the thoracolumbar spine by incorporating spine curvature and muscle morphology measurements from computed tomography (CT) scans to determine the degree to which vertebral compressive and shear loading estimates are sensitive to variations in trunk anatomy. We measured spine curvature and trunk muscle morphology using spine CT scans of 125 men, and then created four different thoracolumbar spine models for each person: (i) height and weight adjusted (Ht/Wt models); (ii) height, weight, and spine curvature adjusted (+C models); (iii) height, weight, and muscle morphology adjusted (+M models); and (iv) height, weight, spine curvature, and muscle morphology adjusted (+CM models). We determined vertebral compressive and shear loading at three regions of the spine (T8, T12, and L3) for four different activities. Vertebral compressive loads predicted by the subject-specific CT-based musculoskeletal models were between 54% lower to 45% higher from those estimated using musculoskeletal models adjusted only for subject height and weight. The impact of subject-specific information on vertebral loading estimates varied with the activity and spinal region. Vertebral loading estimates were more sensitive to incorporation of subject-specific spinal curvature than subject-specific muscle morphology. Our results indicate that individual variations in spine curvature and trunk muscle morphology can have a major impact on estimated vertebral compressive and shear loads, and thus should be accounted for when estimating subject-specific vertebral loading. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2164-2173, 2017.

Evaluation of a new approach to compute intervertebral disc height measurements from lateral radiographic views of the spine.

PURPOSE: Current standard methods to quantify disc height, namely distortion compensated Roentgen analysis (DCRA), have been mostly utilized in the lumbar and cervical spine and have strict exclusion criteria. Specifically, discs adjacent to a vertebral fracture are excluded from measurement, thus limiting the use of DCRA in studies that include older populations with a high prevalence of vertebral fractures. Thus, we developed and tested a modified DCRA algorithm that does not depend on vertebral shape. METHODS: Participants included 1186 men and women from the Framingham Heart Study Offspring and Third Generation Multidetector CT Study. Lateral CT scout images were used to place 6 morphometry points around each vertebra at 13 vertebral levels in each participant. Disc heights were calculated utilizing these morphometry points using DCRA methodology and our modified version of DCRA, which requires information from fewer morphometry points than the standard DCRA. RESULTS: Modified DCRA and standard DCRA measures of disc height are highly correlated, with concordance correlation coefficients above 0.999. Both measures demonstrate good inter- and intra-operator reproducibility. 13.9 % of available disc heights were not evaluable or excluded using the standard DCRA algorithm, while only 3.3 % of disc heights were not evaluable using our modified DCRA algorithm. CONCLUSIONS: Using our modified DCRA algorithm, it is not necessary to exclude vertebrae with fracture or other deformity from disc height measurements as in the standard DCRA. Modified DCRA also yields identical measurements to the standard DCRA. Thus, the use of modified DCRA for quantitative assessment of disc height will lead to less missing data without any loss of accuracy, making it a preferred alternative to the current standard methodology.

Optimizing laser-driven proton acceleration from overdense targets.

We demonstrate how to tune the main ion acceleration mechanism in laser-plasma interactions to collisionless shock acceleration, thus achieving control over the final ion beam properties (e. g. maximum energy, divergence, number of accelerated ions). We investigate this technique with three-dimensional particle-in-cell simulations and illustrate a possible experimental realisation. The setup consists of an isolated solid density target, which is preheated by a first laser pulse to initiate target expansion, and a second one to trigger acceleration. The timing between the two laser pulses allows to access all ion acceleration regimes, ranging from target normal sheath acceleration, to hole boring and collisionless shock acceleration. We further demonstrate that the most energetic ions are produced by collisionless shock acceleration, if the target density is near-critical, ne ≈ 0.5 ncr. A scaling of the laser power shows that 100 MeV protons may be achieved in the PW range.

Direct Observation of the Injection Dynamics of a Laser Wakefield Accelerator Using Few-Femtosecond Shadowgraphy.

We present few-femtosecond shadowgraphic snapshots taken during the nonlinear evolution of the plasma wave in a laser wakefield accelerator with transverse synchronized few-cycle probe pulses. These snapshots can be directly associated with the electron density distribution within the plasma wave and give quantitative information about its size and shape. Our results show that self-injection of electrons into the first plasma-wave period is induced by a lengthening of the first plasma period. Three-dimensional particle-in-cell simulations support our observations.

Full characterization of the amplified spontaneous emission from a diode-pumped high-power laser system.

We present the first complete temporal and spatial characterization of the amplified spontaneous emission (ASE) of laser radiation generated by a diode-pumped high-power laser system. The ASE of the different amplifiers was measured independently from the main pulse and was characterized within a time window of -10ms ≤ t ≤ 10ms and an accuracy of up to 15fs around the main pulse. Furthermore, the focusability and the energy of the ASE from each amplifier was measured after recompression. Using our analysis method, the laser components, which need to be optimized for a further improvement of the laser contrast, can be identified. This will be essential for laser-matter interaction experiments requiring a minimized ASE intensity or fluence.

K-shell spectroscopy of silicon ions as diagnostic for high electric fields.

We developed a detection scheme, capable of measuring X-ray line shape of tracer ions in µm thick layers at the rear side of a target foil irradiated by ultra intense laser pulses. We performed simulations of the effect of strong electric fields on the K-shell emission of silicon and developed a spectrometer dedicated to record this emission. The combination of a cylindrically bent crystal in von Hámos geometry and a CCD camera with its single photon counting capability allows for a high dynamic range of the instrument and background free spectra. This approach will be used in future experiments to study electric fields of the order of TV/m at high density plasmas close to solid density.

All-reflective, highly accurate polarization rotator for high-power short-pulse laser systems.

We present the setup of a polarization rotating device and its adaption for high-power short-pulse laser systems. Compared to conventional halfwave plates, the all-reflective principle using three zero-phase shift mirrors provides a higher accuracy and a higher damage threshold. Since plan-parallel plates, e.g. these halfwave plates, generate postpulses, which could lead to the generation of prepulses during the subsequent laser chain, the presented device avoids parasitic pulses and is therefore the preferable alternative for high-contrast applications. Moreover the device is easily scalable for large beam diameters and its spectral reflectivity can be adjusted by an appropriate mirror coating to be well suited for ultra-short laser pulses.

Harmonic generation from relativistic plasma surfaces in ultrasteep plasma density gradients.

Harmonic generation in the limit of ultrasteep density gradients is studied experimentally. Observations reveal that, while the efficient generation of high order harmonics from relativistic surfaces requires steep plasma density scale lengths (L(p)/λ < 1), the absolute efficiency of the harmonics declines for the steepest plasma density scale length L(p)→0, thus demonstrating that near-steplike density gradients can be achieved for interactions using high-contrast high-intensity laser pulses. Absolute photon yields are obtained using a calibrated detection system. The efficiency of harmonics reflected from the laser driven plasma surface via the relativistic oscillating mirror was estimated to be in the range of 10(-4)-10(-6) of the laser pulse energy for photon energies ranging from 20-40 eV, with the best results being obtained for an intermediate density scale length.

Note: A large aperture four-mirror reflective wave-plate for high-intensity short-pulse laser experiments.

We report on a four-mirror reflective wave-plate system based on a phase-shifting mirror (PSM) for a continuous variation of elliptical polarization without changing the beam position and direction. The system presented and characterized here can replace a conventional retardation plate providing all advantages of a PSM, such as high damage-threshold, large scalability, and low dispersion. This makes reflective wave-plates an ideal tool for ultra-high power laser applications.

Compact cryogenic source of periodic hydrogen and argon droplet beams for relativistic laser-plasma generation.

We present a cryogenic source of periodic streams of micrometer-sized hydrogen and argon droplets as ideal mass-limited target systems for fundamental intense laser-driven plasma applications. The highly compact design combined with a high temporal and spatial droplet stability makes our injector ideally suited for experiments using state-of-the-art high-power lasers in which a precise synchronization between the laser pulses and the droplets is mandatory. We show this by irradiating argon droplets with multi-terawatt pulses.

Measurement of magnetic-field structures in a laser-wakefield accelerator.

Experimental measurements of magnetic fields generated in the cavity of a self-injecting laser-wakefield accelerator are presented. Faraday rotation is used to determine the existence of multimegagauss fields, constrained to a transverse dimension comparable to the plasma wavelength ∼λp and several λp longitudinally. The fields are generated rapidly and move with the driving laser. In our experiment, the appearance of the magnetic fields is correlated with the production of relativistic electrons, indicating that they are inherently tied to the growth and wave breaking of the nonlinear plasma wave. This evolution is confirmed by numerical simulations, showing that these measurements provide insight into the wakefield evolution with high spatial and temporal resolution.

Fast advection of magnetic fields by hot electrons.

Experiments where a laser-generated proton beam is used to probe the megagauss strength self-generated magnetic fields from a nanosecond laser interaction with an aluminum target are presented. At intensities of 10(15) W cm(-2) and under conditions of significant fast electron production and strong heat fluxes, the electron mean-free-path is long compared with the temperature gradient scale length and hence nonlocal transport is important for the dynamics of the magnetic field in the plasma. The hot electron flux transports self-generated magnetic fields away from the focal region through the Nernst effect [A. Nishiguchi, Phys. Rev. Lett. 53, 262 (1984)] at significantly higher velocities than the fluid velocity. Two-dimensional implicit Vlasov-Fokker-Planck modeling shows that the Nernst effect allows advection and self-generation transports magnetic fields at significantly faster than the ion fluid velocity, v(N)/c(s)≈10.

Observation of a long-wavelength hosing modulation of a high-intensity laser pulse in underdense plasma.

We report the first experimental observation of a long-wavelength hosing modulation of a high-intensity laser pulse. Side-view images of the scattered optical radiation at the fundamental wavelength of the laser reveal a transverse oscillation of the laser pulse during its propagation through underdense plasma. The wavelength of the oscillation λ(hosing) depends on the background plasma density n(e) and scales as λ(hosing)∼n(e)(-3/2). Comparisons with an analytical model and two-dimensional particle-in-cell simulations reveal that this laser hosing can be induced by a spatiotemporal asymmetry of the intensity distribution in the laser focus which can be caused by a misalignment of the parabolic focusing mirror or of the diffraction gratings in the pulse compressor.

Establishment of technical prerequisites for cell irradiation experiments with laser-accelerated electrons.

PURPOSE: In recent years, laser-based acceleration of charged particles has rapidly progressed and medical applications, e.g., in radiotherapy, might become feasible in the coming decade. Requirements are monoenergetic particle beams with long-term stable and reproducible properties as well as sufficient particle intensities and a controlled delivery of prescribed doses at the treatment site. Although conventional and laser-based particle accelerators will administer the same dose to the patient, their different time structures could result in different radiobiological properties. Therefore, the biological response to the ultrashort pulse durations and the resulting high peak dose rates of these particle beams have to be investigated. The technical prerequisites, i.e., a suitable cell irradiation setup and the precise dosimetric characterization of a laser-based particle accelerator, have to be realized in order to prepare systematic cell irradiation experiments. METHODS: The Jena titanium:sapphire laser system (JETI) was customized in preparation for cell irradiation experiments with laser-accelerated electrons. The delivered electron beam was optimized with regard to its spectrum, diameter, dose rate, and dose homogeneity. A custom-designed beam and dose monitoring system, consisting of a Roos ionization chamber, a Faraday cup, and EBT-1 dosimetry films, enables real-time monitoring of irradiation experiments and precise determination of the dose delivered to the cells. Finally, as proof-of-principle experiment cell samples were irradiated using this setup. RESULTS: Laser-accelerated electron beams, appropriate for in vitro radiobiological experiments, were generated with a laser shot frequency of 2.5 Hz and a pulse length of 80 fs. After laser acceleration in the helium gas jet, the electrons were filtered by a magnet, released from the vacuum target chamber, and propagated in air for a distance of 220 mm. Within this distance a lead collimator (aperture of 35 mm) was introduced, leading, along with the optimized setup, to a beam diameter of 35 mm, sufficient for the irradiation of common cell culture vessels. The corresponding maximum dose inhomogeneity over the beam spot was less than 10% for all irradiated samples. At cell position, the electrons posses a mean kinetic energy of 13.6 MeV, a bunch length of about 5 ps (FWHM), and a mean pulse dose of 1.6 mGy/bunch. Cross correlations show clear linear dependencies for the online recorded accumulated bunch charges, pulse doses, and pulse numbers on absolute doses determined with EBT-1 films. Hence, the established monitoring system is suitable for beam control and a dedicated dose delivery. Additionally, reasonable day-to-day stable and reproducible properties of the electron beam were achieved. CONCLUSIONS: Basic technical prerequisites for future cell irradiation experiments with ultrashort pulsed laser-accelerated electrons were established at the JETI laser system. The implemented online control system is suitable to compensate beam intensity fluctuations and the achieved accuracy of dose delivery to the cells is sufficient for radiobiological cell experiments. Hence, systematic in vitro cell irradiation experiments can be performed, being the first step toward clinical application of laser-accelerated particles. Further steps, including the transfer of the established methods to experiments on higher biological systems or to other laser-based particle accelerators, will be prepared.