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We present a quintuply lensed z ∼ 6 candidate discovered in the field of the galaxy cluster RXC J2248.7−4431 (z ∼ 0.348) targeted within the Cluster Lensing and Supernova survey with Hubble (CLASH) and selected in the deep Hubble Space Telescope (HST) frontier fields survey. Thanks to the CLASH 16-band HST imaging, we identify the quintuply lensed z ∼ 6 candidate as an optical dropout in the inner region of the cluster, the brightest image having magAB = 24.8 ± 0.1 in the f105w filter. We perform a detailed photometric analysis to verify its high-z and lensed nature. We get as photometric redshift zph ∼ 5.9, and given the extended nature and NIR colours of the lensed images, we rule out low-z early-type and galactic star contaminants. We perform a strong lensing analysis of the cluster, using 13 families of multiple lensed images identified in the HST images. Our final best model predicts the high-z quintuply lensed system with a position accuracy of 0.8 arcsec. The magnifications of the five images are between 2.2 and 8.3, which leads to a delensed UV luminosity of $L_{1600}\sim 0.5L_{1600}^*$ at z = 6. We also estimate the UV slope from the observed NIR colours, finding a steep β = −2.89 ± 0.38. We use singular and composite stellar population SEDs to fit the photometry of the high-z candidate, and we conclude that it is a young (age <300 Myr) galaxy with mass of M ∼ 108 M⊙, subsolar metallicity (Z < 0.2 Z⊙) and low dust content (AV ∼ 0.2–0.4). [ABSTRACT FROM AUTHOR]

The development of novel therapeutic proteins is a lengthy and costly process, with an average attrition rate of 91% (Thomas et al. Clinical Development Success Rates and Contributing Factors 2011-2020, 2021). To increase the probability of success and ensure robust drug supply beyond approval, it is essential to assess the developability profile of new potential drug candidates as early and broadly as possible in development (Jain et al. MAbs, 2023. https://doi.org/10.1016/j.copbio.2011.06.002 ). Predicting these properties in silico is expected to be the next leap in innovation as it would enable significantly reduced development timelines combined with broader screens at lower costs. However, developing predictive algorithms typically requires substantial datasets generated under very defined conditions, a limiting factor especially for new classes of therapeutic proteins that hold immense clinical promise. Here we describe a strategy for assessing the developability of a novel class of small therapeutic Anticalin® proteins using machine learning in conjunction with a knowledge-driven approach. The knowledge-driven approach considers developability attributes such as aggregation propensity, charge variants, immunogenicity, specificity, thermal stability, hydrophobicity, and potential post-translational modifications, to calculate a holistic developability score. Based on sequence-derived descriptors as input parameters we established novel statistical models designed to predict the developability scores for Anticalin proteins. The best models yielded low root mean square errors across the entire dataset and were further validated by removing input data from individual screening campaigns and predicting developability scores for those drug candidates. The adoption of the described workflow will enable significantly streamlined preclinical development of Anticalin drug candidates and could potentially be applied to other therapeutic protein scaffolds., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

White light generation (WLG) in bulk material can be used as a versatile broadband seed source for optical parametric chirped pulse amplification (OPCPA) stages. In this case, it is beneficial to optimize the performance of the WLG seeder in combination with the subsequent OPCPA stage. Here, we characterize how small variations in the drive pulse energy affect the white light seeder performance, in particular the wavelength stability of the amplified OPCPA spectrum. To isolate the influence of drive pulse energy on the OPCPA central wavelength, we introduce a phase-sensitive amplitude measurement and carefully optimize the drive pulse focus position (at the bulk) to minimize the sensitivity to the jitter of the drive pulse energy. With additional active stabilization of the delay between pump and seed pulses in the OPCPA, we achieve a central wavelength jitter of 2 × 10 -4 . With this performance, our source is an ideal front-end for applications in laser-plasma acceleration or free-electron laser seeding.

Extreme heat loads on optics, in particular the final pulse compression gratings, are a major hurdle to overcome in the ongoing push towards high average power (kW) and high repetition rate (kHz) operation of terawatt-class Ti:sapphire lasers. Multilayer dielectric (MLD) diffraction gratings have been suggested as a potential alternative to traditionally gold-coated compressor gratings, which are plagued by high energy absorption in the top gold layer. However, to support the required bandwidth (and ultimately the desired pulse duration) with MLD gratings, the gratings have to be operated in an out-of-plane geometry near the Littrow angle. Here, we report on the design of an MLD-based out-of-plane test compressor and a matching custom stretcher. We present a full characterization of the MLD compressor, focusing on its spectral transmission and the significance of laser pulse polarization in the out-of-plane geometry. To demonstrate compression of 40 μJ pulses centered at 800 nm wavelength to 26 fs pulse duration, we use the compressor with an MLD and gold grating configuration, and fully characterize the compressed pulses. Extrapolating our results indicates that MLD-grating-based out-of-plane compressors can support near-transform-limited pulses with sub-30 fs duration and good quality, demonstrating the viability of this concept for kW-level ultrafast Ti:sapphire laser systems.

Ultrafast laser systems, such as optical parametric chirped pulse amplifiers (OPCPA), are complex tools. Optimizing laser performance for a given application is often plagued by intricate couplings between different output parameters, making simultaneous control of multiple pulse properties difficult. Here, we experimentally demonstrate an autonomous tuning procedure of a white-light seeded two-stage OPCPA using an evolutionary strategy to reliably reach an optimized working point. We use the data collected during the tuning procedure to calibrate a performance model of the laser system, which we then apply to stabilize the intricately coupled laser output energy and spectrum simultaneously. Our approach ensures reliable day-to-day operation at optimized working points without manual tuning. We demonstrate shot-to-shot energy stability of <0.18 % rms, in combination with <25 pm rms wavelength stability and <0.2 % rms bandwidth stability during multi-day operation.

Frequency doubling of a Q-switched Yb-doped rod-type 4 × 4 multicore fiber (MCF) laser system is reported. A second harmonic generation (SHG) efficiency of up to 52% was achieved with type I non-critically phase-matched lithium triborate (LBO), with a total SHG pulse energy of up to 17 mJ obtained at 1 kHz repetition rate. The dense parallel arrangement of amplifying cores into a shared pump cladding enables a significant increase in the energy capacity of active fibers. The frequency-doubled MCF architecture is compatible with high-repetition-rate and high-average-power operation and may provide an efficient alternative to bulk solid-state systems as pump sources for high-energy titanium-doped sapphire lasers.

Ultrafast laser pulses featuring both high spatio-temporal beam quality and excellent energy stability are crucial for many applications. Here, we present a seed laser with high beam quality and energy stability, based on a collinear optical parametric chirped pulse amplification (OPCPA) stage, delivering 46 µJ pulses with a 25 fs Fourier limit at 1 kHz repetition rate. While saturation of the OPCPA stage is necessary for achieving the highest possible energy stability, it also leads to a degradation of the beam quality. Using simulations, we show that spectrally dependent, rotationally symmetric aberrations dominate the collinear OPCPA in saturation. We experimentally characterize these aberrations and then remove distinct spatial frequencies to greatly improve the spectral homogeneity of the beam quality, while keeping an excellent energy stability of 0.2 % rms measured over 70 hours.

Applications of laser-plasma accelerators demand low energy spread beams and high-efficiency operation. Achieving both requires flattening the accelerating fields by controlled beam loading of the plasma wave. Here, we optimize the generation of an electron bunch via localized ionization injection, such that the combination of injected current profile and averaged acceleration dynamics results in optimal beam loading conditions. This enables the reproducible production of 1.2% rms energy spread bunches with 282 MeV and 44 pC at an estimated energy-transfer efficiency of ∼19%. We correlate shot-to-shot variations to reveal the phase space dynamics and train a neural network that predicts the beam quality as a function of the drive laser.

High average power high-intensity laser systems can suffer from a heat-induced deformation of the final compressor gratings, which introduces wavefront aberrations and spatio-temporal couplings to the pulse. Here, we use a simple numerical description, that was first introduced by Li et al. (Appl. Phys. Express, 10, 102702, 2017 and Optics Express, 26, 8453, 2018), to calculate the resulting degradation of the peak intensity and the 3-dimensional deformation of the laser pulse as a function of average power, and verify the results using experimental data. For a typical 100 TW-class laser we find that non-negligible pulse distortions can occur at an average power as low as 2.7 Watts. An open source implementation of our numerical description is available for researchers to estimate the effects of spatio-temporal couplings for their specific laser configuration.

Highly-efficient optical generation of narrowband terahertz radiation enables unexplored technologies and sciences from compact electron acceleration to charge manipulation in solids. State-of-the-art conversion efficiencies are currently achieved using difference-frequency generation driven by temporal beating of chirped pulses but remain, however, far lower than desired or predicted. Here we show that high-order spectral phase fundamentally limits the efficiency of narrowband difference-frequency generation using chirped-pulse beating and resolve this limitation by introducing a novel technique based on tuning the relative spectral phase of the pulses. For optical terahertz generation, we demonstrate a 13-fold enhancement in conversion efficiency for 1%-bandwidth, 0.361 THz pulses, yielding a record energy of 0.6 mJ and exceeding previous optically-generated energies by over an order of magnitude. Our results prove the feasibility of millijoule-scale applications like terahertz-based electron accelerators and light sources and solve the long-standing problem of temporal irregularities in the pulse trains generated by interfering chirped pulses.

High-repetition-rate high-power laser systems induce a high average power heat deposition into the gold-coated diffraction gratings. To study the effects of the thermal expansion of in-vacuum Pyrex gratings on the laser properties, we scan the pulse energy and repetition rate of a 200 TW laser system while monitoring the laser wavefront. Through the measured changes in laser divergence and focusability, we define an average power limit below which the in-vacuum compressor can be used with no degradation of the laser focus quality.

The molecular mechanism by which the microtubule-associated protein (MAP) tau regulates the formation of microtubules (MTs) is poorly understood. The activity of tau is controlled via phosphorylation at specific Ser/Thr sites. Of those phosphorylation sites, 17 precede a proline, making them potential recognition sites for the peptidyl-prolyl isomerase Pin1. Pin1 binding and catalysis of phosphorylated tau at the AT180 epitope, which was implicated in Alzheimer's disease, has been reported to be crucial for restoring tau's ability to promote MT polymerization in vitro and in vivo [1]. Surprisingly, we discover that Pin1 does not promote phosphorylated tau-induced MT formation in vitro, refuting the commonly accepted model in which Pin1 binding and catalysis on the A180 epitope restores the function of the Alzheimer's associated phosphorylated tau in tubulin assembly [1, 2]. Using turbidity assays, time-resolved small angle X-ray scattering (SAXS), and time-resolved negative stain electron microscopy (EM), we investigate the mechanism of tau-mediated MT assembly and the role of the Thr231 and Ser235 phosphorylation on this process. We discover novel GTP-tubulin ring-shaped species, which are detectable in the earliest stage of tau-induced polymerization and may play a crucial role in the early nucleation phase of MT assembly. Finally, by NMR and SAXS experiments, we show that the tau molecules must be located on the surface of MTs and tubulin rings during the polymerization reaction. The interaction between tau and tubulin is multipartite, with a high affinity interaction of the four tubulin-binding repeats, and a weaker interaction with the proline-rich sequence and the termini of tau., (Copyright © 2016. Published by Elsevier Ltd.)

Human peptidyl-prolyl isomerase (PPIase) Pin1 plays key roles in developmental processes, cell proliferation, and neuronal function. Extensive phosphorylation of the microtubule binding protein tau has been implicated in neurodegeneration and Alzheimer's disease. For the past 15years, these two players have been the focus of an enormous research effort to unravel the biological relevance of their interplay in health and disease, resulting in a series of proposed molecular mechanism of how Pin1 catalysis of tau results in biological phenotypes. Our results presented here refute these mechanisms of Pin1 action. Using NMR, isothermal calorimetry (ITC), and small angle x-ray scattering (SAXS), we dissect binding and catalysis on multiple phosphorylated tau with particular emphasis toward the Alzheimer's associated AT180 tau epitope containing phosphorylated THR231 and SER235. We find that phosphorylated (p-) SER235-PRO, but not pTHR231-PRO, is exclusively catalyzed by full-length Pin1 and isolated PPIase domain. Importantly, site-specific measurements of Pin1-catalysis of CDK2/CycA-phosphorylated full-length tau reveal a number of sites that are catalyzed simultaneously with different efficiencies. Furthermore, we show that the turnover efficiency at pSER235 by Pin1 is independent of both the WW domain and phosphorylation on THR231. Our mechanistic results on site-specific binding and catalysis together with the lack of an increase of dephosphorylation rates by PP2A counter a series of previously published models for the role of Pin1 catalysis of tau in Alzheimer's disease. Together, our data reemphasize the complicated scenario between binding and catalysis of multiple phosphorylated tau by Pin1 and the need for directly linking biological phenotypes and residue-specific turnover in Pin1 substrates., (Copyright © 2016. Published by Elsevier Ltd.)

Botulinum neurotoxins (BoNTs) are highly potent bacterial proteins that block neurotransmitter release at the neuromuscular junction by cleaving SNAREs (soluble N-ethyl maleimide sensitive factor attachment protein receptors). However, their serotype A (BoNT/A) that cleaves SNAP-25 (synaptosomal-associated protein of 25 kDa) has also been an established pharmaceutical for treatment of medical conditions that rely on hyperactivity of cholinergic nerve terminals for 25 years. The expansion of its use to a variety of further medical conditions associated with hypersecretion components is prevented partly because the involved SNARE isoforms are not cleaved. Therefore, we examined by mutational analyses the reason for the resistance of human SNAP-23, an isoform of SNAP-25. We show that replacement of 10 SNAP-23 residues with their SNAP-25 counterparts effects SNAP-25-like cleavability. Conversely, transfer of each of the replaced SNAP-23 residues to SNAP-25 drastically decreased the cleavability of SNAP-25. By means of the existing SNAP-25-toxin co-crystal structure, molecular dynamics simulations, and corroborative mutagenesis studies, the appropriate binding pockets for these residues in BoNT/A were characterized. Systematic mutagenesis of two major BoNT/A binding pockets was conducted in order to adapt these pockets to corresponding amino acids of human SNAP-23. Human SNAP-23 cleaving mutants were isolated using a newly established yeast-based screening system. This method may be useful for engineering novel BoNT/A pharmaceuticals for the treatment of diseases that rely on SNAP-23-mediated hypersecretion., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Clinical information is often used for biomedical research. Data warehouses can help providing researchers with data and the opportunity to find eligible participants for clinical trials., Objectives: To define an information platform for healthcare and biomedical research based on requirements by clinicians and researchers., Methods: Interviews with clinicians, researchers, data privacy officers, IT and hospital administration combined with a questionnaire sent to 60 medical departments at our hospital were conducted., Results: Resulting requirements were grouped and a platform architecture was designed based on the requirements., Conclusion: Requirements lead to a single platform supporting both, patient care and biomedical research.

Secondary use or single source is still far from routine in healthcare, although lots of data are available either structured or unstructured. As data are stored in multiple systems, using them for biomedical research is difficult. Clinical data warehouses already help overcoming this issue, but currently they are only used for certain parts of biomedical research. A comprehensive research platform based on a generic architecture pattern could increase the benefits of existing data warehouses for both patient care and research by meeting two objectives: serving as a so called single point-of-truth and acting as a mediator between them strengthening interaction and close collaboration. Another effect is to reduce boundaries for the implementation of data warehouses. Taking further settings into account the architecture of a clinical data warehouse supporting patient care and biomedical research needs to be integrated with biomaterial banks and other sources. This work provides a solution conceptualizing a comprehensive architecture pattern of a Health Information Research Platform (HIReP) derived from use cases of the patient care and biomedical research domain. It serves as single IT infrastructure providing solutions for any type of use case.

Botulinum neurotoxins (BoNTs) block neurotransmitter release by proteolyzing SNARE proteins in peripheral nerve terminals. Entry into neurons occurs subsequent to interaction with gangliosides and a synaptic vesicle protein. Isoforms I and II of synaptotagmin were shown to act as protein receptors for two of the seven BoNT serotypes, BoNT/B and BoNT/G, and for mosaic-type BoNT/DC. BoNT/B and BoNT/G exhibit a homologous binding site for synaptotagmin whose interacting part adopts helical structure upon binding to BoNT/B. Whereas the BoNT/B-synaptotagmin-II interaction has been elucidated in molecular detail, corresponding information about BoNT/G is lacking. Here we systematically mutated the synaptotagmin binding site in BoNT/G and performed a comparative binding analysis with mutants of the cell binding subunit of BoNT/B. The results suggest that synaptotagmin takes the same overall orientation in BoNT/B and BoNT/G governed by the strictly conserved central parts of the toxins' binding site. The surrounding nonconserved areas differently contribute to receptor binding. Reciprocal mutations Y1186W and L1191Y increased the level of binding of BoNT/G approximately to the level of BoNT/B affinity, suggesting a similar synaptotagmin-bound state. The effects of the mutations were confirmed by studying the activity of correspondingly mutated full-length BoNTs. On the basis of these data, molecular modeling experiments were employed to reveal an atomistic model of BoNT/G-synaptotagmin recognition. These data suggest a reduced length and/or a bend in the C-terminal part of the synaptotagmin helix that forms upon contact with BoNT/G as compared with BoNT/B and are in agreement with the data of the mutational analyses.

The amide synthase of the geldanamycin producer, Streptomyces hygroscopicus, shows a broader chemoselectivity than the corresponding amide synthase present in Actinosynnema pretiosum, the producer of the highly cytotoxic ansamycin antibiotics, the ansamitocins. This was demonstrated when blocked mutants of both strains incapable of biosynthesizing 3-amino-5-hydroxybenzoic acid (AHBA), the polyketide synthase starter unit of both natural products, were supplemented with 3-amino-5-hydroxymethylbenzoic acid instead. Unlike the ansamitocin producer A. pretiosum, S. hygroscopicus processed this modified starter unit not only to the expected 19-membered macrolactams but also to ring enlarged 20-membered macrolactones. The former mutaproducts revealed the sequence of transformations catalyzed by the post-PKS tailoring enzymes in geldanamycin biosynthesis. The unprecedented formation of the macrolactones together with molecular modeling studies shed light on the mode of action of the amide synthase responsible for macrocyclization. Obviously, the 3-hydroxymethyl substituent shows similar reactivity and accessibility toward C-1 of the seco-acid as the arylamino group, while phenolic hydroxyl groups lack this propensity to act as nucleophiles in the macrocyclization. The promiscuity of the amide synthase of S. hygroscopicus was further demonstrated by successful feeding of four other m-hydroxymethylbenzoic acids, leading to formation of the expected 20-membered macrocycles. Good to moderate antiproliferative activities were encountered for three of the five new geldanamycin derivatives, which matched well with a competition assay for Hsp90α., (© 2011 American Chemical Society)