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Background: Genetic testing for Huntington's disease (HD) was initially usually positive but more recently the negative rate has increased: patients with negative HD tests are described as having HD phenocopy syndromes (HDPC). This study examines their clinical characteristics and investigates the genetic causes of HDPC., Methods: Clinical data from neurogenetics clinics and HDPC gene-panel data were analysed. Additionally, a subset of 50 patients with HDPC underwent whole-genome sequencing (WGS) analysed via Expansion Hunter and Ingenuity Variant Analysis., Results: HDPC prevalence was estimated at 2.3-2.9 per 100 000. No clinical discriminators between patients with HD and HDPC could be identified. In the gene-panel data, deleterious variants and potentially deleterious variants were over-represented in cases versus controls. WGS analysis identified one ATXN1 expansion in a patient with HDPC., Conclusions: The HDPC phenotype is consistent with HD, but the genotype is distinct. Both established deleterious variants and novel potentially deleterious variants in genes related to neurodegeneration contribute to HDPC., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Repeat expansion disorders (REDs) are a devastating group of predominantly neurological diseases. Together they are common, affecting 1 in 3,000 people worldwide with population-specific differences. However, prevalence estimates of REDs are hampered by heterogeneous clinical presentation, variable geographic distributions and technological limitations leading to underascertainment. Here, leveraging whole-genome sequencing data from 82,176 individuals from different populations, we found an overall disease allele frequency of REDs of 1 in 283 individuals. Modeling disease prevalence using genetic data, age at onset and survival, we show that the expected number of people with REDs would be two to three times higher than currently reported figures, indicating underdiagnosis and/or incomplete penetrance. While some REDs are population specific, for example, Huntington disease-like 2 in Africans, most REDs are represented in all broad genetic ancestries (that is, Europeans, Africans, Americans, East Asians and South Asians), challenging the notion that some REDs are found only in specific populations. These results have worldwide implications for local and global health communities in the diagnosis and counseling of REDs., (© 2024. The Author(s).)

On-chip integration of 2D materials with unique structures and properties endow integrated devices with new functionalities and improved performance. With high flexibility in ways to modify its properties and compatibility with integrated platforms, graphene oxide (GO) is an exceptionally attractive 2D material for hybrid integrated photonic chips. Here, by harnessing unique property changes induced by photothermal effects in 2D GO films, novel functionalities beyond the capability of photonic integrated circuits are demonstrated. These include all-optical control and tuning, optical power limiting, and nonreciprocal light transmission. The 2D layered GO films are integrated onto photonic chips with precise control of their thickness and size. Benefitting from the broadband optical response of 2D GO films, all three functionalities feature a very wide operational optical bandwidth. By fitting the experimental results with theory, the changes in GO film properties induced by the photothermal effects are analyzed, revealing interesting insights about the physics of 2D GO films. These results highlight the versatility of 2D GO films in implementing new functions for integrated photonic devices for a wide range of applications., (© 2024 The Author(s). Advanced Materials published by Wiley‐VCH GmbH.)

We study the interaction of a laser cavity-soliton microcomb with an externally coupled, co-propagating tunable CW pump, observing parametric Kerr interactions which lead to the formation of both a cross-phase modulation and a four-wave mixing replica of the laser cavity-soliton. We compare and explain the dependence of the microcomb spectra from both the cavity-soliton and pump parameters, demonstrating the ability to adjust the microcomb externally without breaking or interfering with the soliton state. The parametric nature of the process agrees with numerical simulations. The parametric extended state maintains the typical robustness of laser-cavity solitons.

We report a dual-polarization radio frequency (RF) channelizer based on microcombs. Two high-Q micro-ring resonators (MRRs) with slightly different free spectral ranges (FSRs) are used: one MRR is pumped to yield soliton crystal microcombs ("active"), and the other MRR is used as a "passive" periodic optical filter supporting dual-polarization operation to slice the RF spectrum. With the tailored mismatch between the FSRs of the active and passive MRRs, wideband RF spectra can be channelized into multiple segments featuring digital-compatible bandwidths via the Vernier effect. Due to the use of dual-polarization states, the number of channelized spectral segments, and thus the RF instantaneous bandwidth (with a certain spectral resolution), can be doubled. In our experiments, we used 20 microcomb lines with ∼ 49 GHz FSR to achieve 20 channels for each polarization, with high RF spectra slicing resolutions at 144 MHz (TE) and 163 MHz (TM), respectively; achieving an instantaneous RF operation bandwidth of 3.1 GHz (TE) and 2.2 GHz (TM). Our approach paves the path towards monolithically integrated photonic RF receivers (the key components - active and passive MRRs are all fabricated on the same platform) with reduced complexity, size, and unprecedented performance, which is important for wide RF applications with digital-compatible signal detection.

Repeat expansion disorders (REDs) are monogenic diseases caused by a sequence of repetitive DNA expanding above a pathogenic threshold. A common feature of the REDs is a strong genotype-phenotype correlation in which a major determinant of age at onset (AAO) and disease progression is the length of the inherited repeat tract. Over a disease-gene carrier's life, the length of the repeat can expand in somatic cells, through the process of somatic expansion which is hypothesised to drive disease progression. Despite being monogenic, individual REDs are phenotypically variable, and exploring what genetic modifying factors drive this phenotypic variability has illuminated key pathogenic mechanisms that are common to this group of diseases. Disease phenotypes are affected by the cognate gene in which the expansion is found, the location of the repeat sequence in coding or non-coding regions and by the presence of repeat sequence interruptions. Human genetic data, mouse models and in vitro models have implicated the disease-modifying effect of DNA repair pathways via the mechanisms of somatic mutation of the repeat tract. As such, developing an understanding of these pathways in the context of expanded repeats could lead to future disease-modifying therapies for REDs., (© 2023 The Author(s).)

The engineering of thermo-optic effects has found broad applications in integrated photonic devices, facilitating efficient light manipulation to achieve various functionalities. Here, we perform both an experimental characterization and a theoretical analysis of these effects in integrated microring resonators made from high-index doped silica, which have had many applications in integrated photonics and nonlinear optics. By fitting the experimental results with theory, we obtain fundamental parameters that characterize their thermo-optic performance, including the thermo-optic coefficient, the efficiency of the optically induced thermo-optic process, and the thermal conductivity. The characteristics of these parameters are compared to those of other materials commonly used for integrated photonic platforms, such as silicon, silicon nitride, and silica. These results offer a comprehensive insight into the thermo-optic properties of doped silica-based devices. Understanding these properties is essential for efficiently controlling and engineering them in many practical applications.

Soliton crystals are a novel form of microcomb, with relatively high conversion efficiency, good thermal robustness, and simple initiation among the methods to generate them. Soliton crystals can be easily generated in microring resonators with an appropriate mode-crossing. However, fabrication defects can significantly affect the mode-crossing placement and strength in devices. To enable soliton crystal states to be harnessed for a broader range of microcomb applications, we need a better understanding of the link between mode-crossing properties and the desired soliton crystal properties. Here, we investigate how to generate the same soliton crystal state in two different microrings, how changes in microring temperature change the mode-crossing properties, and how mode-crossing properties affect the generation of our desired soliton crystal state. We find that temperature affects the mode-crossing position in these rings but without major changes in the mode-crossing strength. We find that our wanted state can be generated over a device temperature range of 25 ∘ C, with different mode-crossing properties, and is insensitive to the precise mode-crossing position between resonances.

RF photonic transversal signal processors, which combine reconfigurable electrical digital signal processing and high-bandwidth photonic processing, provide a powerful solution for achieving adaptive high-speed information processing. Recent progress in optical microcomb technology provides compelling multi-wavelength sources with a compact footprint, yielding a variety of microcomb-based RF photonic transversal signal processors with either discrete or integrated components. Although they operate based on the same principle, the processors in these two forms exhibit distinct performances. This paper presents a comparative investigation of their performances. First, we compare the performances of state-of-the-art processors, focusing on the processing accuracy. Next, we analyze various factors that contribute to the performance differences, including the tap number and imperfect response of experimental components. Finally, we discuss the potential for future improvement. These results provide a comprehensive comparison of microcomb-based RF photonic transversal signal processors implemented using discrete and integrated components and provide insights for their future development.

Although frequently hypothesized, the evidence for associations between affect and marijuana use in everyday life remains ambiguous. Inconsistent findings across existing work may be due, in part, to differences in study design and analytic decisions, such as study inclusion criteria, the operationalization of affect, or the timing of affect assessment. We used specification curves to assess the robustness of the evidence for affect predicting same-day marijuana use and marijuana use predicting next-day affect across several hundred models that varied in terms of decisions that reflect those typical in this literature (e.g., whether to average affect prior to marijuana use or select the affect report closest in time to marijuana use). We fitted these curves to data from two ecological momentary assessment studies of regular marijuana and/or alcohol using college students ( N = 287). Results provided robust evidence that marijuana use was slightly less likely following experiences of negative affect and slightly more likely following positive affect. Specification curves suggested that differences in previous findings are most likely a function of the specific emotion items used to represent affect rather than differences in inclusion criteria, the temporal assessment and modeling of affect, or the covariates added to the model. There was little evidence for an association between marijuana use and next-day affect. Overall, our findings provide evidence against the predictions made by affect reinforcement models in college students and suggest that future research should model the associations of marijuana use with discrete emotional states rather than general negative and positive affect. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Graphene oxide (GO) was initially developed to emulate graphene, but it was soon recognized as a functional material in its own right, addressing an application space that is not accessible to graphene and other carbon materials. Over the past decade, research on GO has made tremendous advances in material synthesis and property tailoring. These, in turn, have led to rapid progress in GO-based photonics, electronics and optoelectronics, paving the way for technological breakthroughs with exceptional performance. In this Review, we provide an overview of the optical, electrical and optoelectronic properties of GO and reduced GO on the basis of their chemical structures and fabrication approaches, together with their applications in key technologies such as solar energy harvesting, energy storage, medical diagnosis, image display and optical communications. We also discuss the challenges of this field, together with exciting opportunities for future technological advances., (© 2023. Springer Nature Limited.)

All-optical signal processing based on nonlinear optical devices is promising for ultrafast information processing in optical communication systems. Recent advances in two-dimensional (2D) layered materials with unique structures and distinctive properties have opened up new avenues for nonlinear optics and the fabrication of related devices with high performance. This paper reviews the recent advances in research on third-order optical nonlinearities of 2D materials, focusing on all-optical processing applications in the optical telecommunications band near 1550 nm. First, we provide an overview of the material properties of different 2D materials. Next, we review different methods for characterizing the third-order optical nonlinearities of 2D materials, including the Z-scan technique, third-harmonic generation (THG) measurement, and hybrid device characterization, together with a summary of the measured n 2 values in the telecommunications band. Finally, the current challenges and future perspectives are discussed.

An important step towards the development of treatments for cognitive impairment in ageing and neurodegenerative diseases is to identify genetic and environmental modifiers of cognitive function and understand the mechanism by which they exert an effect. In Huntington's disease, the most common autosomal dominant dementia, a small number of studies have identified intellectual enrichment, i.e. a cognitively stimulating lifestyle and genetic polymorphisms as potential modifiers of cognitive function. The aim of our study was to further investigate the relationship and interaction between genetic factors and intellectual enrichment on cognitive function and brain atrophy in Huntington's disease. For this purpose, we analysed data from Track-HD, a multi-centre longitudinal study in Huntington's disease gene carriers and focused on the role of intellectual enrichment (estimated at baseline) and the genes FAN1 , MSH3 , BDNF , COMT and MAPT in predicting cognitive decline and brain atrophy. We found that carrying the 3a allele in the MSH3 gene had a positive effect on global cognitive function and brain atrophy in multiple cortical regions, such that 3a allele carriers had a slower rate of cognitive decline and atrophy compared with non-carriers, in agreement with its role in somatic instability. No other genetic predictor had a significant effect on cognitive function and the effect of MSH3 was independent of intellectual enrichment. Intellectual enrichment also had a positive effect on cognitive function; participants with higher intellectual enrichment, i.e. those who were better educated, had higher verbal intelligence and performed an occupation that was intellectually engaging, had better cognitive function overall, in agreement with previous studies in Huntington's disease and other dementias. We also found that intellectual enrichment interacted with the BDNF gene, such that the positive effect of intellectual enrichment was greater in Met66 allele carriers than non-carriers. A similar relationship was also identified for changes in whole brain and caudate volume; the positive effect of intellectual enrichment was greater for Met66 allele carriers, rather than for non-carriers. In summary, our study provides additional evidence for the beneficial role of intellectual enrichment and carrying the 3a allele in MSH3 in cognitive function in Huntington's disease and their effect on brain structure., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Laser cavity-soliton microcombs are robust optical pulsed sources, usually implemented with a microresonator-filtered fibre laser. In such a configuration, a nonlinear microcavity converts the narrowband pulse resulting from bandwidth-limited amplification to a background-free broadband microcomb. Here, we theoretically and experimentally study the soliton conversion efficiency between the narrowband input pulse and the two outputs of a four-port integrated microcavity, namely the 'Drop' and 'Through' ports. We simultaneously measure on-chip, single-soliton conversion efficiencies of 45% and 25% for the two broadband comb outputs at the 'Drop' and 'Through' ports of a 48.9 GHz free-spectral range micro-ring resonator, obtaining a total conversion efficiency of 72%.

In many disciplines, states that emerge in open systems far from equilibrium are determined by a few global parameters 1,2 . These states can often mimic thermodynamic equilibrium, a classic example being the oscillation threshold of a laser 3 that resembles a phase transition in condensed matter. However, many classes of states cannot form spontaneously in dissipative systems, and this is the case for cavity solitons 2 that generally need to be induced by external perturbations, as in the case of optical memories 4,5 . In the past decade, these highly localized states have enabled important advancements in microresonator-based optical frequency combs 6,7 . However, the very advantages that make cavity solitons attractive for memories-their inability to form spontaneously from noise-have created fundamental challenges. As sources, microcombs require spontaneous and reliable initiation into a desired state that is intrinsically robust 8-20 . Here we show that the slow non-linearities of a free-running microresonator-filtered fibre laser 21 can transform temporal cavity solitons into the system's dominant attractor. This phenomenon leads to reliable self-starting oscillation of microcavity solitons that are naturally robust to perturbations, recovering spontaneously even after complete disruption. These emerge repeatably and controllably into a large region of the global system parameter space in which specific states, highly stable over long timeframes, can be achieved., (© 2022. The Author(s).)

We experimentally investigate power-sensitive photo-thermal tuning (PTT) of two-dimensional (2D) graphene oxide (GO) films coated on integrated optical waveguides. We measure the light power thresholds for reversible and permanent GO reduction in silicon nitride (SiN) waveguides integrated with one and two layers of GO. For the device with one layer of GO, the power threshold for reversible and permanent GO reduction are ~20 and ~22 dBm, respectively. For the device with two layers of GO, the corresponding results are ~13 and ~18 dBm, respectively. Raman spectra at different positions of a hybrid waveguide with permanently reduced GO are characterized, verifying the inhomogeneous GO reduction along the direction of light propagation through the waveguide. The differences between the PTT induced by a continuous-wave laser and a pulsed laser are also compared, confirming that the PTT mainly depend on the average input power. These results reveal interesting features for 2D GO films coated on integrated optical waveguides, which are of fundamental importance for the control and engineering of GO's properties in hybrid integrated photonic devices.

We experimentally demonstrate enhanced spectral broadening of femtosecond optical pulses after propagation through silicon-on-insulator (SOI) nanowire waveguides integrated with two-dimensional (2D) graphene oxide (GO) films. Owing to the strong mode overlap between the SOI nanowires and the GO films with a high Kerr nonlinearity, the self-phase modulation (SPM) process in the hybrid waveguides is significantly enhanced, resulting in greatly improved spectral broadening of the femtosecond optical pulses. A solution-based, transfer-free coating method is used to integrate GO films onto the SOI nanowires with precise control of the film thickness. Detailed SPM measurements using femtosecond optical pulses are carried out, achieving a broadening factor of up to ~4.3 for a device with 0.4-mm-long, 2 layers of GO. By fitting the experimental results with the theory, we obtain an improvement in the waveguide nonlinear parameter by a factor of ~3.5 and in the effective nonlinear figure of merit (FOM) by a factor of ~3.8, relative to the uncoated waveguide. Finally, we discuss the influence of GO film length on the spectral broadening and compare the nonlinear optical performance of different integrated waveguides coated with GO films. These results confirm the improved nonlinear optical performance of silicon devices integrated with 2D GO films.

With compact footprint, low energy consumption, high scalability, and mass producibility, chip-scale integrated devices are an indispensable part of modern technological change and development. Recent advances in 2D layered materials with their unique structures and distinctive properties have motivated their on-chip integration, yielding a variety of functional devices with superior performance and new features. To realize integrated devices incorporating 2D materials, it requires a diverse range of device fabrication techniques, which are of fundamental importance to achieve good performance and high reproducibility. This paper reviews the state-of-art fabrication techniques for the on-chip integration of 2D materials. First, an overview of the material properties and on-chip applications of 2D materials is provided. Second, different approaches used for integrating 2D materials on chips are comprehensively reviewed, which are categorized into material synthesis, on-chip transfer, film patterning, and property tuning/modification. Third, the methods for integrating 2D van der Waals heterostructures are also discussed and summarized. Finally, the current challenges and future perspectives are highlighted., (© 2022 Wiley-VCH GmbH.)

We report an all-optical radio-frequency (RF) spectrum analyzer with a bandwidth greater than 5 THz, based on a 50 cm long spiral waveguide in a CMOS-compatible high-index doped silica platform. By carefully mapping out the dispersion profile of the waveguides for different thicknesses, we identify the optimal design to achieve near-zero dispersion in the C-band. To demonstrate the capability of the RF spectrum analyzer, we measure the optical output of a femtosecond fiber laser with an ultrafast optical RF spectrum in the terahertz regime.

Convolutional neural networks, inspired by biological visual cortex systems, are a powerful category of artificial neural networks that can extract the hierarchical features of raw data to provide greatly reduced parametric complexity and to enhance the accuracy of prediction. They are of great interest for machine learning tasks such as computer vision, speech recognition, playing board games and medical diagnosis 1-7 . Optical neural networks offer the promise of dramatically accelerating computing speed using the broad optical bandwidths available. Here we demonstrate a universal optical vector convolutional accelerator operating at more than ten TOPS (trillions (10 12 ) of operations per second, or tera-ops per second), generating convolutions of images with 250,000 pixels-sufficiently large for facial image recognition. We use the same hardware to sequentially form an optical convolutional neural network with ten output neurons, achieving successful recognition of handwritten digit images at 88 per cent accuracy. Our results are based on simultaneously interleaving temporal, wavelength and spatial dimensions enabled by an integrated microcomb source. This approach is scalable and trainable to much more complex networks for demanding applications such as autonomous vehicles and real-time video recognition.

With superior optical properties, high flexibility in engineering its material properties, and strong capability for large-scale on-chip integration, graphene oxide (GO) is an attractive solution for on-chip integration of 2D materials to implement functional integrated photonic devices capable of new features. Over the past decade, integrated GO photonics, representing an innovative merging of integrated photonic devices and thin GO films, has experienced significant development, leading to a surge in many applications covering almost every field of optical sciences such as photovoltaics, optical imaging, sensing, nonlinear optics, and light emitting. This paper reviews the recent advances in this emerging field, providing an overview of the optical properties of GO as well as methods for the on-chip integration of GO. The main achievements made in GO hybrid integrated photonic devices for diverse applications are summarized. The open challenges as well as the potential for future improvement are also discussed., (© 2020 Wiley-VCH GmbH.)

The application of gold nanoparticles (AuNPs) in cancer therapeutics and diagnostics has recently reached a clinical level. Functional use of the AuNP in theranostics first requires effective uptake into the cells, but accurate quantification of AuNPs cellular uptake in real-time is still a challenge due to the destructive nature of existing characterization methods. The optical imaging-based quantification method is highly desirable. Here, we propose the use of high-order image correlation spectroscopy (HICS) as an optical imaging-based nanoparticle quantification technique. Coupled with dark field microscopy (DFM), a non-destructive and easy quantification method could be achieved. We demonstrate HICS analysis on 80 nm AuNPs coated with cetyltrimethylammonium bromide (CTAB) uptake in HeLa cells to calculate the percentage of aggregate species (dimer) in the total uptake and their relative scattering quantum yield inside the cells, the details of which are not available with other quantification techniques. The total particle uptake kinetics measured were in a reasonable agreement with the literature., Competing Interests: The authors declare no conflicts of interest., (© 2020 Optical Society of America under the terms of the OSA Open Access Publishing Agreement.)

We demonstrate coherent supercontinuum generation spanning over an octave from a silicon germanium-on-silicon waveguide using ∼200 f s pulses at a wavelength of 4 µm. The waveguide is engineered to provide low all-normal dispersion in the TM polarization. We validate the coherence of the generated supercontinuum via simulations, with a high degree of coherence across the entire spectrum. Such a generated supercontinuum could lend itself to pulse compression down to 22 fs.

Layered two-dimensional (2D) graphene oxide (GO) films are integrated with silicon-on-insulator (SOI) nanowire waveguides to experimentally demonstrate an enhanced Kerr nonlinearity, observed through self-phase modulation (SPM). The GO films are integrated with SOI nanowires using a large-area, transfer-free, layer-by-layer coating method that yields precise control of the film thickness. The film placement and coating length are controlled by opening windows in the silica cladding of the SOI nanowires. Owing to the strong mode overlap between the SOI nanowires and the highly nonlinear GO films, the Kerr nonlinearity of the hybrid waveguides is significantly enhanced. Detailed SPM measurements using picosecond optical pulses show significant spectral broadening enhancement for SOI nanowires coated with 2.2 mm long films of 1-3 layers of GO and 0.4 mm long films with 5-20 layers of GO. By fitting the experimental results with theory, the dependence of GO's Kerr nonlinearity on layer number and pulse energy is obtained, showing interesting physical insights and trends of the layered GO films from 2D monolayers to quasi bulk-like behavior. Finally, we show that by coating SOI nanowires with GO films, the effective nonlinear parameter of SOI nanowires is increased 16-fold, with the effective nonlinear figure of merit (FOM) increasing by about 20 times to FOM > 5. These results reveal the strong potential of using layered GO films to improve the Kerr nonlinear optical performance of silicon photonic devices.

Micro-combs - optical frequency combs generated by integrated micro-cavity resonators - offer the full potential of their bulk counterparts, but in an integrated footprint. They have enabled breakthroughs in many fields including spectroscopy, microwave photonics, frequency synthesis, optical ranging, quantum sources, metrology and ultrahigh capacity data transmission. Here, by using a powerful class of micro-comb called soliton crystals, we achieve ultra-high data transmission over 75 km of standard optical fibre using a single integrated chip source. We demonstrate a line rate of 44.2 Terabits s -1 using the telecommunications C-band at 1550 nm with a spectral efficiency of 10.4 bits s -1 Hz -1 . Soliton crystals exhibit robust and stable generation and operation as well as a high intrinsic efficiency that, together with an extremely low soliton micro-comb spacing of 48.9 GHz enable the use of a very high coherent data modulation format (64 QAM - quadrature amplitude modulated). This work demonstrates the capability of optical micro-combs to perform in demanding and practical optical communications networks.

Layered 2D graphene oxide (GO) films are integrated with micro-ring resonators (MRRs) to experimentally demonstrate enhanced nonlinear optics. Both uniformly coated (1-5 layers) and patterned (10-50 layers) GO films are integrated on complementary-metal-oxide-semiconductor (CMOS)-compatible doped silica MRRs using a large-area, transfer-free, layer-by-layer GO coating method with precise control of the film thickness. The patterned devices further employ photolithography and lift-off processes to enable precise control of the film placement and coating length. Four-wave-mixing (FWM) measurements for different pump powers and resonant wavelengths show a significant improvement in efficiency of ≈7.6 dB for a uniformly coated device with 1 GO layer and ≈10.3 dB for a patterned device with 50 GO layers. The measurements agree well with theory, with the enhancement in FWM efficiency resulting from the high Kerr nonlinearity and low loss of the GO films combined with the strong light-matter interaction within the MRRs. The dependence of GO's third-order nonlinearity on layer number and pump power is also extracted from the FWM measurements, revealing interesting physical insights about the evolution of the GO films from 2D monolayers to quasi bulk-like behavior. These results confirm the high nonlinear optical performance of integrated photonic resonators incorporated with 2D layered GO films., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A broadband graphene-on-Si3N4-membrane photodetector for the visible-IR spectral range is realised by simple lithography and deposition techniques. Photo-current is produced upon illumination due to presence of the build-in potential between dissimilar metal electrodes on graphene as a result of charge transfer. The sensitivity of the photo-detector is ∼ 1 . 1 μ A/W when irradiated with 515 and 1030 nm wavelengths; a smaller separation between the metal contacts favors gradient formation of the built-in electric field and increases the efficiency of charge separation. This optically-thin graphene-on-membrane photodetector and its interdigitated counterpart has the potential to be used within 3D optical elements, such as photonic crystals, sensors, and wearable electronics applications where there is a need to minimise optical losses introduced by the detector.

Background: Huntington disease (HD) is caused by an unstable CAG/CAA repeat expansion encoding a toxic polyglutamine tract. Here, we tested the hypotheses that HD outcomes are impacted by somatic expansion of, and polymorphisms within, the HTT CAG/CAA glutamine-encoding repeat, and DNA repair genes., Methods: The sequence of the glutamine-encoding repeat and the proportion of somatic CAG expansions in blood DNA from participants inheriting 40 to 50 CAG repeats within the TRACK-HD and Enroll-HD cohorts were determined using high-throughput ultra-deep-sequencing. Candidate gene polymorphisms were genotyped using kompetitive allele-specific PCR (KASP). Genotypic associations were assessed using time-to-event and regression analyses., Findings: Using data from 203 TRACK-HD and 531 Enroll-HD participants, we show that individuals with higher blood DNA somatic CAG repeat expansion scores have worse HD outcomes: a one-unit increase in somatic expansion score was associated with a Cox hazard ratio for motor onset of 3·05 (95% CI = 1·94 to 4·80, p = 1·3 × 10 -6 ). We also show that individual-specific somatic expansion scores are associated with variants in FAN1 (pFDR = 4·8 × 10 -6 ), MLH3 (pFDR = 8·0 × 10 -4 ), MLH1 (pFDR = 0·004) and MSH3 (pFDR = 0·009). We also show that HD outcomes are best predicted by the number of pure CAGs rather than total encoded-glutamines., Interpretation: These data establish pure CAG length, rather than encoded-glutamine, as the key inherited determinant of downstream pathophysiology. These findings have implications for HD diagnostics, and support somatic expansion as a mechanistic link for genetic modifiers of clinical outcomes, a driver of disease, and potential therapeutic target in HD and related repeat expansion disorders., Funding: CHDI Foundation., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

The ability of laser systems to emit different adjustable temporal pulse profiles and patterns is desirable for a broad range of applications. While passive mode-locking techniques have been widely employed for the realization of ultrafast laser pulses with mainly Gaussian or hyperbolic secant temporal profiles, the generation of versatile pulse shapes in a controllable way and from a single laser system remains a challenge. Here we show that a nonlinear amplifying loop mirror (NALM) laser with a bandwidth-limiting filter (in a nearly dispersion-free arrangement) and a short integrated nonlinear waveguide enables the realization and distinct control of multiple mode-locked pulsing regimes (e.g., Gaussian pulses, square waves, fast sinusoidal-like oscillations) with repetition rates that are variable from the fundamental (7.63 MHz) through its 205 th harmonic (1.56 GHz). These dynamics are described by a newly developed and compact theoretical model, which well agrees with our experimental results. It attributes the control of emission regimes to the change of the NALM response function that is achieved by the adjustable interplay between the NALM amplification and the nonlinearity. In contrast to previous square wave emissions, we experimentally observed that an Ikeda instability was responsible for square wave generation. The presented approach enables laser systems that can be universally applied to various applications, e.g., spectroscopy, ultrafast signal processing and generation of non-classical light states.

Neuroblastoma is a paediatric cancer with a poor prognosis. This is in part due to widespread metastasis at time of presentation, which is refractory to current treatment modalities. New therapeutic agents that can control not only tumour growth but also metastasis are urgently needed. The differentiation therapy, retinoic acid, is currently used in clinic, leading to terminal differentiation of neuroblastoma cells thus reducing tumour growth in the primary tumour as well as at metastatic sites. However, retinoic acid only works in a subset of patients. We investigated the potential of CDK inhibitors, Palbociclib and RO-3306, on neuroblastoma cell differentiation, tumour progression and metastasis by utilising a 3R compliant cost effective preclinical chick embryo model. In both SK-N-AS and BE(2)C cell lines, when engrafted on the chorioallantoic membrane of chick embryos, we observed a reduction of tumour cell proliferation as well as a reduction in hypoxia preconditioning-driven metastasis by 60%. In addition, the expression of a panel of genes with known roles in metastasis, which increased upon hypoxia-preconditioning, was largely reduced by a CDK1 inhibitor. These results provide a promising alternative to currently existing therapies and might aid the development of new treatment protocols for retinoic acid-resistant patients.

Entanglement witnesses are operators that are crucial for confirming the generation of specific quantum systems, such as multipartite and high-dimensional states. For this reason, many witnesses have been theoretically derived which commonly focus on establishing tight bounds and exhibit mathematical compactness as well as symmetry properties similar to that of the quantum state. However, for increasingly complex quantum systems, established witnesses have lacked experimental achievability, as it has become progressively more challenging to design the corresponding experiments. Here, we present a universal approach to derive entanglement witnesses that are capable of detecting the presence of any targeted complex pure quantum system and that can be customized towards experimental restrictions or accessible measurement settings. Using this technique, we derive experimentally optimized witnesses that are able to detect multipartite d-level cluster states, and that require only two measurement settings. We present explicit examples for customizing the witness operators given different realistic experimental restrictions, including witnesses for high-dimensional entanglement that use only two-dimensional projection measurements. Our work enables us to confirm the presence of probed quantum states using methods that are compatible with practical experimental realizations in different quantum platforms.

Modern optical systems increasingly rely on complex physical processes that require accessible control to meet target performance characteristics. In particular, advanced light sources, sought for, for example, imaging and metrology, are based on nonlinear optical dynamics whose output properties must often finely match application requirements. However, in these systems, the availability of control parameters (e.g., the optical field shape, as well as propagation medium properties) and the means to adjust them in a versatile manner are usually limited. Moreover, numerically finding the optimal parameter set for such complex dynamics is typically computationally intractable. Here, we use an actively controlled photonic chip to prepare and manipulate patterns of femtosecond optical pulses that give access to an enhanced parameter space in the framework of supercontinuum generation. Taking advantage of machine learning concepts, we exploit this tunable access and experimentally demonstrate the customization of nonlinear interactions for tailoring supercontinuum properties.