Reconfigurable integrated photonic filters for optical signal processing using a silicon photonic platform.

We present a systematic photonic filter design approach by deploying pole-zero optimization. The filter transfer function is derived from its specifications by formulating closed-form optimization objective functions and subsequently translating them into optical design parameters. Two distinct filter examples, namely Chebyshev and elliptic filters, are considered for the design and validation. A compact reconfigurable three-pole photonic filter is fabricated on a silicon photonic platform to illustrate the proposed design technique including transmission tunability. Integrated thermal phase shifters coupled with micro-ring resonators are used to reconfigure filter responses. A well-matched experimental demonstration is presented to validate the proposed tuning method. We achieved a sharp out-of-band edge rejection of at least 20 and 40 dB for the elliptic and Chebyshev filter, respectively.

Si/Ge phototransistor with responsivity >1000A/W on a silicon photonics platform.

In this article, we report a Si/Ge waveguide phototransistor with high responsivity and low dark current under low bias voltages, due to an engineered electric field distribution. The photodetector consists of n-i-p-i-n doping regions and shows a responsivity of 606 A/W at 1 V bias, and 1032 A/W at 2.8V bias with an input optical power of -50 dBm, and dark current of 4 µA and 42 µA respectively. This is achieved by placing two p+-doped regions in the silicon slab region beneath the Ge epitaxial layer. A measured small signal -3 dB bandwidth of 1.5 GHz with a -80 dBc/Hz phase noise response at 1 KHz frequency offset were demonstrated experimentally.

Systematic benchmarking of single-cell ATAC-sequencing protocols.

Single-cell assay for transposase-accessible chromatin by sequencing (scATAC-seq) has emerged as a powerful tool for dissecting regulatory landscapes and cellular heterogeneity. However, an exploration of systemic biases among scATAC-seq technologies has remained absent. In this study, we benchmark the performance of eight scATAC-seq methods across 47 experiments using human peripheral blood mononuclear cells (PBMCs) as a reference sample and develop PUMATAC, a universal preprocessing pipeline, to handle the various sequencing data formats. Our analyses reveal significant differences in sequencing library complexity and tagmentation specificity, which impact cell-type annotation, genotype demultiplexing, peak calling, differential region accessibility and transcription factor motif enrichment. Our findings underscore the importance of sample extraction, method selection, data processing and total cost of experiments, offering valuable guidance for future research. Finally, our data and analysis pipeline encompasses 169,000 PBMC scATAC-seq profiles and a best practices code repository for scATAC-seq data analysis, which are freely available to extend this benchmarking effort to future protocols.

Silicon-thulium hybrid microdisk lasers with low threshold and wide emission wavelength range.

We demonstrate low-threshold and wide emission wavelength range hybrid-integrated silicon-thulium microdisk lasers based on a pulley-coupled design. The resonators are fabricated on a silicon-on-insulator platform using a standard foundry process and the gain medium is deposited using a straightforward, low-temperature post-processing step. We show lasing in 40- and 60-µm diameter microdisks with up to 2.6 mW double-sided output power and bidirectional slope efficiencies of up to 13.4% with respect to 1620 nm pump power launched to the bus waveguides. We observe thresholds less than 1 mW versus on-chip pump power and both single-mode and multimode laser emission spanning across wavelengths from 1825 to 1939nm. These low threshold lasers with emissions over a > 100 nm range open the door to monolithic silicon photonic integrated circuits with broadband optical gain and highly compact and efficient light sources in the emerging ∼1.8-2.0 µm wavelength band.

Hybrid silicon-tellurium-dioxide DBR resonators coated in PMMA for biological sensing.

We report on silicon waveguide distributed Bragg reflector (DBR) cavities hybridized with a tellurium dioxide (TeO2) cladding and coated in plasma functionalized poly (methyl methacrylate) (PMMA) for label free biological sensors. We describe the device structure and fabrication steps, including reactive sputtering of TeO2 and spin coating and plasma functionalization of PMMA on foundry processed Si chips, as well as the characterization of two DBR designs via thermal, water, and bovine serum albumin (BSA) protein sensing. Plasma treatment on the PMMA films was shown to decrease the water droplet contact angle from ∼70 to ∼35°, increasing hydrophilicity for liquid sensing, while adding functional groups on the surface of the sensors intended to assist with immobilization of BSA molecules. Thermal, water and protein sensing were demonstrated on two DBR designs, including waveguide-connected sidewall (SW) and waveguide-adjacent multi-piece (MP) gratings. Limits of detection of 60 and 300 × 10-4 RIU were measured via water sensing, and thermal sensitivities of 0.11 and 0.13 nm/°C were measured from 25-50 °C for SW and MP DBR cavities, respectively. Plasma treatment was shown to enable protein immobilization and sensing of BSA molecules at a concentration of 2 µg/mL diluted in phosphate buffered saline, demonstrating a ∼1.6 nm resonance shift and subsequent full recovery to baseline after stripping the proteins with sodium dodecyl sulfate for a MP DBR device. These results are a promising step towards active and laser-based sensors using rare-earth-doped TeO2 in silicon photonic circuits, which can be subsequently coated in PMMA and functionalized via plasma treatment for label free biological sensing.

A spatially resolved atlas of the human lung characterizes a gland-associated immune niche.

Single-cell transcriptomics has allowed unprecedented resolution of cell types/states in the human lung, but their spatial context is less well defined. To (re)define tissue architecture of lung and airways, we profiled five proximal-to-distal locations of healthy human lungs in depth using multi-omic single cell/nuclei and spatial transcriptomics (queryable at lungcellatlas.org ). Using computational data integration and analysis, we extend beyond the suspension cell paradigm and discover macro and micro-anatomical tissue compartments including previously unannotated cell types in the epithelial, vascular, stromal and nerve bundle micro-environments. We identify and implicate peribronchial fibroblasts in lung disease. Importantly, we discover and validate a survival niche for IgA plasma cells in the airway submucosal glands (SMG). We show that gland epithelial cells recruit B cells and IgA plasma cells, and promote longevity and antibody secretion locally through expression of CCL28, APRIL and IL-6. This new 'gland-associated immune niche' has implications for respiratory health.

Application of the TDFA window in true optical time delay systems.

Recent advances in silicon photonic components operating in the thulium-doped fiber amplifier (TDFA) wavelength regime around 2-µm have shown that these wavelengths hold great promise for on-chip photonic systems. Here we present our work on characterizing a Mach-Zehnder interferometer coupled silicon photonic ring resonator operating in the TDFA window for optical time delay applications. We describe the optical transmission and variable time delay properties of the resonator, including a detailed characterization and comparison of the directional coupler and Mach-Zehnder interferometer base components at both 1930 and 1550 nm wavelengths. The results show tuning of a ring from a 190-ps peak time delay at a resonant extinction ratio of 5.1-dB to a 560-ps peak time delay at an extinction ratio of 11.0-dB, in good agreement with optical models of the device. These results demonstrate significant promise towards the future application of TDFA band devices in optical time delay systems.

Robust temporal map of human in vitro myelopoiesis using single-cell genomics.

Myeloid cells are central to homeostasis and immunity. Characterising in vitro myelopoiesis protocols is imperative for their use in research, immunotherapies, and understanding human myelopoiesis. Here, we generate a >470K cells molecular map of human induced pluripotent stem cells (iPSC) differentiation into macrophages. Integration with in vivo single-cell atlases shows in vitro differentiation recapitulates features of yolk sac hematopoiesis, before definitive hematopoietic stem cells (HSC) emerge. The diversity of myeloid cells generated, including mast cells and monocytes, suggests that HSC-independent hematopoiesis can produce multiple myeloid lineages. We uncover poorly described myeloid progenitors and conservation between in vivo and in vitro regulatory programs. Additionally, we develop a protocol to produce iPSC-derived dendritic cells (DC) resembling cDC2. Using CRISPR/Cas9 knock-outs, we validate the effects of key transcription factors in macrophage and DC ontogeny. This roadmap of myeloid differentiation is an important resource for investigating human fetal hematopoiesis and new therapeutic opportunities.

MultiMAP: dimensionality reduction and integration of multimodal data.

Multimodal data is rapidly growing in many fields of science and engineering, including single-cell biology. We introduce MultiMAP, a novel algorithm for dimensionality reduction and integration. MultiMAP can integrate any number of datasets, leverages features not present in all datasets, is not restricted to a linear mapping, allows the user to specify the influence of each dataset, and is extremely scalable to large datasets. We apply MultiMAP to single-cell transcriptomics, chromatin accessibility, methylation, and spatial data and show that it outperforms current approaches. On a new thymus dataset, we use MultiMAP to integrate cells along a temporal trajectory. This enables quantitative comparison of transcription factor expression and binding site accessibility over the course of T cell differentiation, revealing patterns of expression versus binding site opening kinetics.

A map of transcriptional heterogeneity and regulatory variation in human microglia.

Microglia, the tissue-resident macrophages of the central nervous system (CNS), play critical roles in immune defense, development and homeostasis. However, isolating microglia from humans in large numbers is challenging. Here, we profiled gene expression variation in primary human microglia isolated from 141 patients undergoing neurosurgery. Using single-cell and bulk RNA sequencing, we identify how age, sex and clinical pathology influence microglia gene expression and which genetic variants have microglia-specific functions using expression quantitative trait loci (eQTL) mapping. We follow up one of our findings using a human induced pluripotent stem cell-based macrophage model to fine-map a candidate causal variant for Alzheimer's disease at the BIN1 locus. Our study provides a population-scale transcriptional map of a critically important cell for human CNS development and disease.

Thulium-doped tellurium oxide waveguide amplifier with 7.6 dB net gain on a silicon nitride chip: publisher's note.

This publisher's note contains corrections to Opt. Lett.44, 5788 (2019)OPLEDP0146-959210.1364/OL.44.005788.

Subwavelength grating metamaterial waveguides functionalized with tellurium oxide cladding.

We report on the design, fabrication and characterization of subwavelength grating metamaterial waveguides coated with tellurium oxide. The structures are first fabricated using a standard CMOS compatible process on a silicon-on-insulator platform. Amorphous tellurium oxide top cladding material is then deposited via post-process RF magnetron sputtering. The photonic bandstructure is controlled by adjustment of the device geometry, opening a wide range of operating regimes, including subwavelength propagation, slow light and the photonic bandgap, for various wavelength bands within the 1550 nm telecommunications window. Propagation loss of 1.0 ± 0.1 dB/mm is reported for the tellurium oxide-cladded device, compared to 1.5 ± 0.1 dB/mm propagation loss reported for the silicon dioxide-cladded reference structure. This is the first time that a high-index (n > 2) oxide cladding has been demonstrated for subwavelength grating metamaterial waveguides, thus introducing a new material platform for on-chip integrated optics.

High-speed performance of a TDFA-band micro-ring resonator modulator and detector.

We demonstrate a silicon-on-insulator micro-ring resonator (MRR) modulator and defect-mediated (DM) detector operating at a wavelength near 2 µm for use in the thulium doped fiber amplifier wavelength band. The MRR modulator was critically coupled with an unbiased notch-depth of 20 dB and Q-factor of 4700. The resonance shift under reverse bias was 23 pm/V with a calculated VπLπ of 2.2 to 2.6 V·cm from -1 to -8 V, respectively. Simulations are in good agreement with the measured data. The experimental modulation bandwidth was 12.5 GHz, limited by the response of the commercial external detector used for this measurement. The DM detector was operated in avalanche mode, had 1.97 µm wavelength responsivities of 0.04 and 0.14 A/W, and had bandwidths greater than 16 and 7.5 GHz at -15 and -30 V biases, respectively. Large-signal measurement demonstrated open eye-diagrams at 5, 10, and 12.5 Gbps for the DM detector and also for an optical link consisting of the modulator and detector integrated on the same silicon chip.

Graphene oxide integrated silicon photonics for detection of vapour phase volatile organic compounds.

The optical response of a graphene oxide integrated silicon micro-ring resonator (GOMRR) to a range of vapour phase Volatile Organic Compounds (VOCs) is reported. The response of the GOMRR to all but one (hexane) of the VOCs tested is significantly higher than that of the uncoated (control) silicon MRR, for the same vapour flow rate. An iterative Finite Difference Eigenmode (FDE) simulation reveals that the sensitivity of the GO integrated device (in terms of RIU/nm) is enhanced by a factor of ~2, which is coupled with a lower limit of detection. Critically, the simulations reveal that the strength of the optical response is determined by molecular specific changes in the local refractive index probed by the evanescent field of the guided optical mode in the device. Analytical modelling of the experimental data, based on Hill-Langmuir adsorption characteristics, suggests that these changes in the local refractive index are determined by the degree of molecular cooperativity, which is enhanced for molecules with a polarity that is high, relative to their kinetic diameter. We believe this reflects a molecular dependent capillary condensation within the graphene oxide interlayers, which, when combined with highly sensitive optical detection, provides a potential route for discriminating between different vapour phase VOCs.

Souporcell: robust clustering of single-cell RNA-seq data by genotype without reference genotypes.

Methods to deconvolve single-cell RNA-sequencing (scRNA-seq) data are necessary for samples containing a mixture of genotypes, whether they are natural or experimentally combined. Multiplexing across donors is a popular experimental design that can avoid batch effects, reduce costs and improve doublet detection. By using variants detected in scRNA-seq reads, it is possible to assign cells to their donor of origin and identify cross-genotype doublets that may have highly similar transcriptional profiles, precluding detection by transcriptional profile. More subtle cross-genotype variant contamination can be used to estimate the amount of ambient RNA. Ambient RNA is caused by cell lysis before droplet partitioning and is an important confounder of scRNA-seq analysis. Here we develop souporcell, a method to cluster cells using the genetic variants detected within the scRNA-seq reads. We show that it achieves high accuracy on genotype clustering, doublet detection and ambient RNA estimation, as demonstrated across a range of challenging scenarios.

Publisher Correction: Single-cell RNA-sequencing of differentiating iPS cells reveals dynamic genetic effects on gene expression.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Correction to: Niacin-mediated rejuvenation of macrophage/microglia enhances remyelination of the aging central nervous system.

The article Niacin­mediated rejuvenation of macrophage/microglia enhances remyelination of the aging central nervous system, written by Khalil S. Rawji, Adam M.H. Young, Tanay Ghosh, Nathan J. Michaels, Reza Mirzaei, Janson Kappen, Kathleen L. Kolehmainen, Nima Alaeiilkhchi, Brian Lozinski, Manoj K. Mishra, Annie Pu, Weiwen Tang, Salma Zein, Deepak K. Kaushik, Michael B. Keough, Jason R. Plemel, Fiona Calvert, Andrew J. Knights, Daniel J. Gaffney, Wolfram Tetzlaff, Robin J. M. Franklin and V. Wee Yong, was originally published electronically on the publisher's internet.

Single-cell RNA-sequencing of differentiating iPS cells reveals dynamic genetic effects on gene expression.

Recent developments in stem cell biology have enabled the study of cell fate decisions in early human development that are impossible to study in vivo. However, understanding how development varies across individuals and, in particular, the influence of common genetic variants during this process has not been characterised. Here, we exploit human iPS cell lines from 125 donors, a pooled experimental design, and single-cell RNA-sequencing to study population variation of endoderm differentiation. We identify molecular markers that are predictive of differentiation efficiency of individual lines, and utilise heterogeneity in the genetic background across individuals to map hundreds of expression quantitative trait loci that influence expression dynamically during differentiation and across cellular contexts.

Niacin-mediated rejuvenation of macrophage/microglia enhances remyelination of the aging central nervous system.

Remyelination following CNS demyelination restores rapid signal propagation and protects axons; however, its efficiency declines with increasing age. Both intrinsic changes in the oligodendrocyte progenitor cell population and extrinsic factors in the lesion microenvironment of older subjects contribute to this decline. Microglia and monocyte-derived macrophages are critical for successful remyelination, releasing growth factors and clearing inhibitory myelin debris. Several studies have implicated delayed recruitment of macrophages/microglia into lesions as a key contributor to the decline in remyelination observed in older subjects. Here we show that the decreased expression of the scavenger receptor CD36 of aging mouse microglia and human microglia in culture underlies their reduced phagocytic activity. Overexpression of CD36 in cultured microglia rescues the deficit in phagocytosis of myelin debris. By screening for clinically approved agents that stimulate macrophages/microglia, we have found that niacin (vitamin B3) upregulates CD36 expression and enhances myelin phagocytosis by microglia in culture. This increase in myelin phagocytosis is mediated through the niacin receptor (hydroxycarboxylic acid receptor 2). Genetic fate mapping and multiphoton live imaging show that systemic treatment of 9-12-month-old demyelinated mice with therapeutically relevant doses of niacin promotes myelin debris clearance in lesions by both peripherally derived macrophages and microglia. This is accompanied by enhancement of oligodendrocyte progenitor cell numbers and by improved remyelination in the treated mice. Niacin represents a safe and translationally amenable regenerative therapy for chronic demyelinating diseases such as multiple sclerosis.