Cross-disorder and disease-specific pathways in dementia revealed by single-cell genomics.

The development of successful therapeutics for dementias requires an understanding of their shared and distinct molecular features in the human brain. We performed single-nuclear RNA-seq and ATAC-seq in Alzheimer's disease (AD), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP), analyzing 41 participants and ∼1 million cells (RNA + ATAC) from three brain regions varying in vulnerability and pathological burden. We identify 32 shared, disease-associated cell types and 14 that are disease specific. Disease-specific cell states represent glial-immune mechanisms and selective neuronal vulnerability impacting layer 5 intratelencephalic neurons in AD, layer 2/3 intratelencephalic neurons in FTD, and layer 5/6 near-projection neurons in PSP. We identify disease-associated gene regulatory networks and cells impacted by causal genetic risk, which differ by disorder. These data illustrate the heterogeneous spectrum of glial and neuronal compositional and gene expression alterations in different dementias and identify therapeutic targets by revealing shared and disease-specific cell states.

Instantaneous frequency measurement system based on quantum dash mode-locked laser.

We present the theory and experimental results of a microwave photonic (MWP) filter based instantaneous frequency measurement system. A quantum dash mode-locked laser is used as an optical frequency comb source. With up to 41 flat comb lines and a real-time feedback loop for comb shaping, a set of MWP filters with linear frequency responses for either linear unit or dB unit are experimentally demonstrated. The maximum measurement frequency can be up to 20 GHz limited by the available test-and-measurement instruments. By using one MWP filter, the root-mean-square error is 51∼66 MHz, which can be improved to 42.2 MHz for linear unit, and 30.7 MHz for dB unit by using two MWP filters together.

Performance of quantum-dash mode-locked lasers (QD-MLLDs) for high-capacity coherent optical communications.

We investigate the capabilities and limitations of quantum-dash mode-locked lasers (QD-MLLDs) as optical frequency comb sources in coherent optical communication systems. We demonstrate that QD-MLLDs are on par with conventional single-wavelength narrow linewidth laser sources and can support high symbol rates and modulation formats. We manage to transmit 64 quadrature amplitude modulation (QAM) signals up to 80 GBd over 80 km of standard single-mode fiber (SSMF), which highlights the distinctive phase noise performance of the QD-MLLD. Using a 38.5 GHz (6 dB bandwidth) silicon photonic (SiP) modulator, we achieve a maximum symbol rate of 104 GBd with 16QAM signaling and a maximum net rate of 416 Gb/s per carrier in a single polarization setup and after 80 km-SSMF transmission. We also compare QD-MLLD performance with commercial narrow-linewidth integrable tunable laser assemblies (ITLAs) and explore their potential for use as local oscillators (LOs) and signal carriers. The QD-MLLD has 45 comb lines usable for transmission at a frequency spacing of 25 GHz, and an RF linewidth of 35 kHz.

IRS-assisted vehicular visible light communications systems: channel modeling and performance analysis.

Visible light communications (VLC) is a promising solution as an alternative for the fully occupied radio frequency bands in the near future. The rear (tail) and front of vehicles have lamps that can be used for vehicular visible light communications (VVLC) systems. However, one of the main challenges of VLC systems is the line-of-sight (LoS) blockage issue. In this paper, we propose the installation of intelligent reflecting surfaces (IRSs) (i.e., smart mirrors) on the back of vehicles to overcome the issue in VVLC systems. We assume three different patterns of angular distribution for the radiation intensity: a commercially available LED with an asymmetrical pattern (Philips Luxeon Rebel), a symmetrical Lambertian pattern, and an asymmetrical Gaussian pattern. In the first section of this paper, we obtain the channel model for the IRS-assisted VVLC systems, then we investigate the path loss results versus link distance under different conditions such as weather type (clear, rainy, moderate fog, and thick fog) and radiation patterns. Moreover, the impact of system parameters such as the aperture size of the photodetector (PD), side-to-side and front-to-front distances, the number of IRS elements, and the IRS area are studied. In the second part, we derive a closed-form expression for the maximum achievable link distance versus the probability of error for the IRS-assisted VVLC systems. In addition, in this section we analyze the impact of the parameters in a single-photon avalanche diode (SPAD), background noise, and the system parameters for the path loss.

Polarization independent Bragg gratings using tilted subwavelength grating waveguide Bragg gratings.

We propose and experimentally demonstrate a polarization independent subwavelength grating (SWG) waveguide Bragg grating (WBG) by using an SWG waveguide with tilted segments. By optimizing the tilting angle and other geometry parameters, such as the width and the length of the loading segments used to create the BG, we can obtain a zero birefringence tilted SWG waveguide and consequently, a polarization independent SWG WBG. In our simulations, the optimal tilting angle is ∼ 58°, whereas the optimal angle obtained in fabrication is ∼ 46°. This deviation is mainly due to fabrication errors, e.g., on the sidewall angle of the silicon segments. For the optimal tilting angle of 46°, the characterized Bragg wavelengths of the TE and TM modes are both ∼ 1517 nm. We believe that the proposed device can have applications in optical communications and interconnections.

AL-aided AMC in a multi-user white-light OFDMA VLC system over a light-diffusing fiber loop.

To develop an adaptive modulation scheme for flexible high-speed multi-user visible light communication (VLC), automatic modulation classification (AMC) is adopted for monitoring the modulation formats of different subcarrier groups. An AMC scheme based on a joint convolutional neural network (CNN), active learning (AL), and data augmentation (DA) is demonstrated over an orthogonal frequency division multiplexing access (OFDMA) VLC system. The configuration of the diffuse white-light VLC system is combined with a pair integrated transceiver module, a light-diffusing fiber (LDF), and a wireless channel, which can provide white-light illumination and ubiquitous access. Within the forward error correction (FEC) threshold, the data rates of the white-light VLC links can reach 325.5 Mbps with a bit error rate (BER) of 2.163 × 10-3. An experiment with two-user access via the proposed VLC link with an unequal bandwidth allocation was demonstrated. The performance of the AL-aided CNN AMC scheme also shows a classification accuracy rate of 95.48% for the constellation diagrams of different subcarriers of the OFDMA signal over 240 training samples and faster convergence than a CNN-based AMC.

Photonic beamforming using a quantum-dash optical frequency comb source.

We demonstrate photonic beamforming using a quantum-dash (QD) optical frequency comb (OFC) source. Thanks to the 25 GHz free spectral range (FSR) and up to 40 comb lines available from the QD OFC, we can implement phased antenna arrays (PAAs) with directional radiation and scanning. We consider two types of PAAs: a uniform linear array (ULA) and a uniform planar array (UPA). By selecting different comb lines with a programmable optical filter, we can tune the FSR of the OFC source and realize a discrete scanning function. We evaluate the beam squint of the ULAs, and the results show that we can achieve broadband operation. Finally, we show that we can achieve both directional radiation and scanning simultaneously using the UPA.

Reduced perceptual narrowing in synesthesia.

Synesthesia is a neurologic trait in which specific inducers, such as sounds, automatically elicit additional idiosyncratic percepts, such as color (thus "colored hearing"). One explanation for this trait-and the one tested here-is that synesthesia results from unusually weak pruning of cortical synaptic hyperconnectivity during early perceptual development. We tested the prediction from this hypothesis that synesthetes would be superior at making discriminations from nonnative categories that are normally weakened by experience-dependent pruning during a critical period early in development-namely, discrimination among nonnative phonemes (Hindi retroflex /d̪a/ and dental /ɖa/), among chimpanzee faces, and among inverted human faces. Like the superiority of 6-mo-old infants over older infants, the synesthetic groups were significantly better than control groups at making all the nonnative discriminations across five samples and three testing sites. The consistent superiority of the synesthetic groups in making discriminations that are normally eliminated during infancy suggests that residual cortical connectivity in synesthesia supports changes in perception that extend beyond the specific synesthetic percepts, consistent with the incomplete pruning hypothesis.

Electrically reconfigurable waveguide Bragg grating filters.

We propose and demonstrate an electrically reconfigurable waveguide Bragg grating filters in silicon-on-insulator using a multiple-contact heater element. There are six electrical pads connected to the heater element in an equidistant manner. These electrical pads allow to create different heat, and corresponding refractive index, distributions across the grating so that the local Bragg wavelength corresponding to the heated segments can be controlled. In turn, this control over the heat distribution allows the device to be reconfigured to implement different filter spectral responses. These filters are applicable for both wavelength division multiplexing systems and optical signal processing applications. As a verification, we demonstrate the generation of two (or more) separate filter bands with a spacing up to 35 nm or a Fabry-Pérot cavity with a 1.6 nm free-spectral range. Moreover, we explain a firm and accurate simulation framework of the proposed device based on COMSOL Multiphysics and the transfer matrix method, which is in excellent agreement with our experimental measurements.

Reconfigurable microwave photonic filter based on a quantum dash mode-locked laser.

We demonstrate a reconfigurable microwave photonic (MWP) filter using a quantum dash (QDash) mode-locked laser (MLL) that can generate an optical frequency comb (OFC) with ∼50 comb lines and a free spectral range of 25 GHz. Thanks to the large number of comb lines, the MWP filter responses can be easily programmed by tailoring the OFC spectrum. We implement MWP filter responses with Gaussian, sinc, flat-top, and multiple peaks, as well as demonstrate that tuning of the central frequency. We achieve a minimum 3 dB bandwidth of ∼100 MHz for a sinc-shaped MWP filter, while the maximum out-of-band rejection can be up to ∼30 dB with Gaussian apodization. Our results show that the QDash-MLL is a promising OFC source for developing integrated and reconfigurable MWP filters.

Dual-frequency optoelectronic oscillator incorporating a single cavity and multiband microwave photonic filter.

Dual-frequency optoelectronic oscillators (OEOs) have potential applications in dual-band wireless networking and dual-parameter sensing systems. We propose a dual-frequency OEO incorporating a multiband microwave photonic filter (MPF). In particular, the two microwave signals are generated simultaneously in a single OEO cavity. By simply varying the parameters of optical spectral slicing and sampling (e.g., with a programmable optical filter) used to implement the MPF, we can readily achieve simultaneous tuning of the dual-frequency output, as well as alternate switching between single-frequency and dual-frequency output. The multi-passband nature of the MPF, enabled via optical spectral slicing, opens a path to multi-frequency OEO operation by scaling our scheme in the future. Such a structure provides a flexible way to generate simultaneously tunable and reconfigurable multi-frequency microwave signals.

Polarization-dependent tuning of Bragg reflection enabled through tilted subwavelength grating waveguide Bragg gratings.

We propose and demonstrate experimentally tilted subwavelength grating (SWG) waveguide Bragg gratings (WBGs). By tilting the SWG segments and optimizing the duty cycle, we can achieve polarization-dependent tuning of the spectral response of the SWG WBG, namely, the spectral response of the fundamental transverse electric (TE) mode shifts toward shorter wavelengths, while that for the transverse magnetic (TM) mode remains almost unchanged. In particular, for tilting angles of 5° and 30°, we can obtain a blueshift in the Bragg wavelength of 7 and 35 nm for the TE mode, while the Bragg wavelength for the TM mode remains within 0.5 nm. The proposed tilted SWG WBGs provide a novel method to manage polarization and/or obtain polarization-dependent wavelength selectivity with integrated WBG devices.

On-chip optical true time delay lines based on subwavelength grating waveguides.

An optical true time delay line (OTTDL) is a fundamental building block for signal processing applications in microwave photonics and optical communications. Here, we experimentally demonstrate an index-variable OTTDL based on an array of 40 subwavelength grating (SWG) waveguides in silicon-on-insulator. Each SWG waveguide in the array is 34 mm long and arranged in a serpentine manner; the average incremental delay between waveguides is about 4.7 ps, and the total delay between the first and last waveguides is approximately 181.9 ps. The waveguide array occupies a chip area of ∼6.5mm×8.7mm=56.55mm2. The proposed OTTDLs bring potential advantages in terms of compactness as well as operation versatility to a variety of microwave signal processing applications.

Bacterial Quorum Sensing Signals Promote Large-Scale Remodeling of Lipid Membranes.

We report that N-acyl-l-homoserine lactones (AHLs), a class of nonionic amphiphiles that common bacteria use as signals to coordinate group behaviors, can promote large-scale remodeling in model lipid membranes. Characterization of supported lipid bilayers (SLBs) of the phospholipid 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) by fluorescence microscopy and quartz crystal microbalance with dissipation (QCM-D) reveals the well-studied AHL signal 3-oxo-C12-AHL and its anionic head group hydrolysis product (3-oxo-C12-HS) to promote the formation of long microtubules that can retract into hemispherical caps on the surface of the bilayer. These transformations are dynamic, reversible, and dependent upon the head group structure. Additional experiments demonstrate that 3-oxo-C12-AHL can promote remodeling to form microtubules in lipid vesicles and promote molecular transport across bilayers. Molecular dynamics (MD) simulations predict differences in thermodynamic barriers to translocation of these amphiphiles across a bilayer that are reflected in both the type and extent of reformation and associated dynamics. Our experimental observations can thus be interpreted in terms of accumulation and relief of asymmetric stresses in the inner and outer leaflets of a bilayer upon intercalation and translocation of these amphiphiles. Finally, experiments on Pseudomonas aeruginosa, a pathogen that uses 3-oxo-C12-AHL for cell-to-cell signaling, demonstrate that 3-oxo-C12-AHL and 3-oxo-C12-HS can promote membrane remodeling at biologically relevant concentrations and in the absence of other biosurfactants, such as rhamnolipids, that are produced at high population densities. Overall, these results have implications for the roles that 3-oxo-C12-AHL and its hydrolysis product may play in not only mediating intraspecies bacterial communication but also processes such as interspecies signaling and bacterial control of host-cell response. Our findings also provide guidance that could prove useful for the design of synthetic self-assembled materials that respond to bacteria in ways that are useful in the context of sensing, drug delivery, and in other fundamental and applied areas.

Charge Reduction of Membrane Proteins in Native Mass Spectrometry Using Alkali Metal Acetate Salts.

Native mass spectrometry (MS) provides the capacity to monitor membrane protein complexes and noncovalent binding of ligands and lipids to membrane proteins. The charge states produced by native MS of membrane proteins often result in gas-phase protein unfolding or loss of noncovalent interactions. In an effort to reduce the charge of membrane proteins, we examined the utility of alkali metal salts as a charge-reducing agent. Low concentrations of alkali metal salts caused marked charge reduction in the membrane protein, Erwinia ligand-gated ion channel (ELIC). The charge-reducing effect only occurred for membrane proteins and was detergent-dependent, being most pronounced in long polyethylene glycol (PEG)-based detergents such as C10E5 and C12E8. On the basis of these results, we propose a mechanism for alkali metal charge reduction of membrane proteins. Addition of low concentrations of alkali metals may provide an advantageous approach for charge reduction of detergent-solubilized membrane proteins by native MS.

Maternal antenatal depression and child mental health: Moderation by genomic risk for attention-deficit/hyperactivity disorder.

Maternal antenatal depression strongly influences child mental health but with considerable inter-individual variation that is, in part, linked to genotype. The challenge is to effectively capture the genotypic influence. We outline a novel approach to describe genomic susceptibility to maternal antenatal depression focusing on child emotional/behavioral difficulties. Two cohorts provided measures of maternal depression, child genetic variation, and child mental health symptoms. We constructed a conventional polygenic risk score (PRS) for attention-deficit/hyperactivity disorder (ADHD) (PRSADHD) that significantly moderated the association between maternal antenatal depression and internalizing problems at 60 months (p = 2.94 × 10-4, R2 = .18). We then constructed an interaction PRS (xPRS) based on a subset of those single nucleotide polymorphisms from the PRSADHD that most accounted for the moderation of the association between maternal antenatal depression and child outcome. The interaction between maternal antenatal depression and this xPRS accounted for a larger proportion of the variance in child emotional/behavioral problems than models based on any PRSADHD (p = 5.50 × 10-9, R2 = .27), with similar findings in the replication cohort. The xPRS was significantly enriched for genes involved in neuronal development and synaptic function. Our study illustrates a novel approach to the study of genotypic moderation on the impact of maternal antenatal depression on child mental health and highlights the utility of the xPRS approach. These findings advance our understanding of individual differences in the developmental origins of mental health.

Discretely programmable microwave photonic filter based on temporal Talbot effects.

We propose and experimentally demonstrate a reconfigurable microwave photonic filter based on temporal Talbot effects. The microwave signal is first uniformly sampled by a train of optical pulses through electro-optic intensity modulation. The sampled optical pulses are then directed to a Talbot-based optical signal processor, consisting of an electro-optic temporal phase modulator and a chromatic dispersion line. The Talbot-based microwave photonic filter (TMPF) exploits the inherent properties of the Talbot self-imaging effect for mitigating pulse-to-pulse intensity fluctuations of optical pulses to transmit some fluctuation frequencies and mitigate or entirely block other microwave spectral components. The output microwave signal is finally reconstructed from the processed optical pulses and the resultant RF response is measured by a network analyzer. The TMPF exhibits an RF response with periodic, symmetric-profile passbands whose center frequency and free spectral range (FSR) are defined by the sampling rate and the dispersion value. The filter passbands can be reconfigured electrically, in discrete steps, by adjusting the modulation function of the phase modulator, i.e., without the need for manual adjustment of the optical components. This enables the capability of selection of specific passbands among the primary passbands. The phase modulation function is provided using an arbitrary waveform generator, with the potential for fast tuning of the filter's spectral response. The bandwidth of the filter passband can also be easily customized by adjusting the sampling pulse's temporal width using an optical bandpass filter. Examples of filter performance in various passband configurations are also presented in the time domain to further validate the operation of the filter.

Technique for the measurement of picosecond optical pulses using a non-linear fiber loop mirror and an optical power meter.

A method for measuring picosecond pulse width by using only fiber components and optical power meters is presented. We have shown that the output power splitting ratio of a non-linear fiber loop mirror can be used to extract the full-width half maximum of the optical pulse, assuming a known slowly varying envelope shape and internal phase structure. Theoretical evaluation was carried out using both self-phase and cross-phase modulation approaches, with the latter showing a twofold sensitivity increase, as expected. In the experimental validation, pulses from an actively fiber mode-locked laser at the repetition rate of 10 GHz were incrementally temporally dispersed by using SMF-28 fiber, and then successfully measured over a pulse width range of 2-10 ps, with a resolution of 0.25 ps. This range can be easily extended from 0.25 to 40 ps by selecting different physical setup parameters.

PRS-on-Spark (PRSoS): a novel, efficient and flexible approach for generating polygenic risk scores.

BACKGROUND: Polygenic risk scores (PRS) describe the genomic contribution to complex phenotypes and consistently account for a larger proportion of variance in outcome than single nucleotide polymorphisms (SNPs) alone. However, there is little consensus on the optimal data input for generating PRS, and existing approaches largely preclude the use of imputed posterior probabilities and strand-ambiguous SNPs i.e., A/T or C/G polymorphisms. Our ability to predict complex traits that arise from the additive effects of a large number of SNPs would likely benefit from a more inclusive approach. RESULTS: We developed PRS-on-Spark (PRSoS), a software implemented in Apache Spark and Python that accommodates different data inputs and strand-ambiguous SNPs to calculate PRS. We compared performance between PRSoS and an existing software (PRSice v1.25) for generating PRS for major depressive disorder using a community cohort (N = 264). We found PRSoS to perform faster than PRSice v1.25 when PRS were generated for a large number of SNPs (~ 17 million SNPs; t = 42.865, p = 5.43E-04). We also show that the use of imputed posterior probabilities and the inclusion of strand-ambiguous SNPs increase the proportion of variance explained by a PRS for major depressive disorder (from 4.3% to 4.8%). CONCLUSIONS: PRSoS provides the user with the ability to generate PRS using an inclusive and efficient approach that considers a larger number of SNPs than conventional approaches. We show that a PRS for major depressive disorder that includes strand-ambiguous SNPs, calculated using PRSoS, accounts for the largest proportion of variance in symptoms of depression in a community cohort, demonstrating the utility of this approach. The availability of this software will help users develop more informative PRS for a variety of complex phenotypes.

Prophylactic Central Neck Dissection for Papillary Thyroid Carcinoma with Clinically Uninvolved Central Neck Lymph Nodes: A Systematic Review and Meta-analysis.

BACKGROUND: Central neck dissection and total thyroidectomy are standard treatments for patients with papillary thyroid carcinoma (PTC) with clinically involved central nodes. However, prophylactic central neck dissection (pCND) in patients with clinically uninvolved cN0 has been beneficial in some studies but ineffective in others. We conducted a meta-analysis to evaluate the efficacy and safety of pCND in patients with central neck lymph nodes cN0 PTC. METHODS: The PubMed, EMBASE, Cochrane Library, and Scopus databases and the ClinicalTrials.gov registry were electronically searched for studies published until September 2017. The meta-analysis was conducted to calculate the pooled effect size by using random-effects model. Treatment efficacies were measured by determining locoregional recurrence (LRR). Secondary outcomes included transient recurrent laryngeal nerve (RLN) injury, permanent RLN injury, transient hypocalcemia, and permanent hypocalcemia. RESULTS: Twenty-three retrospective and prospective cohort studies involving 18,376 patients were reviewed. Patients who underwent pCND had significantly lower LRR (odds ratio [OR] 0.65; 95% confidence interval [CI] 0.48-0.88) but significantly higher incidence rates of transient RLN injury (OR 2.03; 95% CI 1.32-3.13), transient hypocalcemia (OR 2.23; 95% CI 1.84-2.70), and permanent hypocalcemia (OR 2.22; 95% CI 1.58-3.13) than that of no pCND group. CONCLUSION: Compared with no pCND, pCND significantly reduces LRR but is accompanied by numerous adverse effects. The clinical decision should be made after the shared decision-making process of clinicians and patients.