Comprehensive analysis of gut microbiota of a healthy population and covariates affecting microbial variation in two large Japanese cohorts.

BACKGROUND: Inter-individual variations in gut microbiota composition are observed even among healthy populations. The gut microbiota may exhibit a unique composition depending on the country of origin and race of individuals. To comprehensively understand the link between healthy gut microbiota and host state, it is beneficial to conduct large-scale cohort studies. The aim of the present study was to elucidate the integrated and non-redundant factors associated with gut microbiota composition within the Japanese population by 16S rRNA sequencing of fecal samples and questionnaire-based covariate analysis. RESULTS: A total of 1596 healthy Japanese individuals participated in this study via two independent cohorts, NIBIOHN cohort (n = 954) and MORINAGA cohort (n = 642). Gut microbiota composition was described and the interaction of these microorganisms with metadata parameters such as anthropometric measurements, bowel habits, medical history, and lifestyle were obtained. Thirteen genera, including Alistipes, Anaerostipes, Bacteroides, Bifidobacterium, Blautia, Eubacterium halli group, Faecalibacterium, Fusicatenibacter, Lachnoclostridium, Parabacteroides, Prevotella_9, Roseburia, and Subdoligranulum were predominant among the two cohorts. On the basis of univariate analysis for overall microbiome variation, 18 matching variables exhibited significant association in both cohorts. A stepwise redundancy analysis revealed that there were four common covariates, Bristol Stool Scale (BSS) scores, gender, age, and defecation frequency, displaying non-redundant association with gut microbial variance. CONCLUSIONS: We conducted a comprehensive analysis of gut microbiota in healthy Japanese individuals, based on two independent cohorts, and obtained reliable evidence that questionnaire-based covariates such as frequency of bowel movement and specific dietary habit affects the microbial composition of the gut. To our knowledge, this was the first study to investigate integrated and non-redundant factors associated with gut microbiota among Japanese populations.

Gut microbial composition in patients with atrial fibrillation: effects of diet and drugs.

Atrial fibrillation (AF) reduces the quality of life by triggering stroke and heart failure. The association between AF onset and gut metabolites suggests a causal relationship between AF and gut microbiota dysbiosis; however, the relationship remains poorly understood. We prospectively enrolled 34 hospitalized patients with AF and 66 age-, sex-, and comorbidity-matched control subjects without a history of AF. Gut microbial compositions were evaluated by amplicon sequencing targeting the 16S ribosomal RNA gene. We assessed differences in dietary habits by using a brief-type self-administered diet history questionnaire (BDHQ). Gut microbial richness was lower in AF patients, although the diversity of gut microbiota did not differ between the two groups. At the genus level, Enterobacter was depleted, while Parabacteroides, Lachnoclostridium, Streptococcus, and Alistipes were enriched in AF patients compared to control subjects. The BDHQ revealed that the intake of n-3 polyunsaturated fatty acids and eicosadienoic acid was higher in AF patients. Our results suggested that AF patients had altered gut microbial composition in connection with dietary habits.

Relationship between Nutrient Intake and Human Gut Microbiota in Monozygotic Twins.

Background and Objectives: The gut microbiota is associated with human health and dietary nutrition. Various studies have been reported in this regard, but it is difficult to clearly analyze human gut microbiota as individual differences are significant. The causes of these individual differences in intestinal microflora are genetic and/or environmental. In this study, we focused on differences between identical twins in Japan to clarify the effects of nutrients consumed on the entire gut microbiome, while excluding genetic differences. Materials and Methods: We selected healthy Japanese monozygotic twins for the study and confirmed their zygosity by matching 15 short tandem repeat loci. Their fecal samples were subjected to 16S rRNA sequencing and bioinformatics analyses to identify and compare the fluctuations in intestinal bacteria. Results: We identified 12 genera sensitive to environmental factors, and found that Lactobacillus was relatively unaffected by environmental factors. Moreover, we identified protein, fat, and some nutrient intake that can affect 12 genera, which have been identified to be more sensitive to environmental factors. Among the 12 genera, Bacteroides had a positive correlation with retinol equivalent intake (rs = 0.38), Lachnospira had a significantly negative correlation with protein, sodium, iron, vitamin D, vitamin B6, and vitamin B12 intake (rs = -0.38, -0.41, -0.39, -0.63, -0.42, -0.49, respectively), Lachnospiraceae ND3007 group had a positive correlation with fat intake (rs = 0.39), and Lachnospiraceae UCG-008 group had a negative correlation with the saturated fatty acid intake (rs = -0.45). Conclusions: Our study is the first to focus on the relationship between human gut microbiota and nutrient intake using samples from Japanese twins to exclude the effects of genetic factors. These findings will broaden our understanding of the more intuitive relationship between nutrient intake and the gut microbiota and can be a useful basis for finding useful biomarkers that contribute to human health.

2 × 2 16-ch silicon photonics wavelength-selective switch based on waveguide gratings.

We demonstrate a 2 × 2 16-ch silicon photonics wavelength-selective switch consisting of contra-directional couplers and thermo-optic Mach-Zehnder switches. The contra-directional couplers are based on sidewall corrugated Bragg gratings with an unlimited free spectral range and thus enable the device to operate over a very wide wavelength range of the C- and L-band. We obtain a fiber-to-fiber insertion loss of 9.2 dB, an on-chip loss of 5.4 dB, a 3-dB bandwidth of 4.2 nm, a bar-port extinction of 15.0 dB, and a cross-port extinction of 23.0 dB, all in 16-ch average. An average trimming power for the bar states and an average switching power for the cross states are 3.8 mW (σ = 2.3 mW) and 15.6 mW (σ = 2.1 mW), respectively. The wavelength dependence of the spectral responses and the resonant effect from the apodization are discussed in detail to show how to further improve the spectral performance.

Inter-layer light transition in hybrid III-V/Si waveguides integrated by µ-transfer printing.

We demonstrate low-loss and broadband light transition from III-V functional layers to a Si platform via two-stage adiabatic-crossing coupler waveguides. A 900-µm-long and 2.7-µm-thick III-V film waveguide consisting of a GaInAsP core and InP cladding layers is transferred onto an air-cladding Si photonic chip by the µ-transfer printing (µ-TP) method. An average optical coupling loss per joint of 1.26 dB is obtained in C + L telecommunication bands (1530-1635 nm). The correlation between alignment offset and measured optical coupling loss is discussed with the frequency distribution of µ-TP samples. We also performed a photoluminescence measurement to investigate the material properties in the GaInAsP layer to see if they are distorted by the strong bending stress produced during the pick-up and print steps of the µ-TP process. The peak intensity reduction of 80-90% and a wavelength shift of 0-5 nm (blue shift) were observed after the process. The series of fundamental studies presented here, which combine multiple analyses, contribute to improving our understanding of III-V/Si photonic integration by µ-TP.

Impact of quality trimming on the efficiency of reads joining and diversity analysis of Illumina paired-end reads in the context of QIIME1 and QIIME2 microbiome analysis frameworks.

BACKGROUND: To increase the accuracy of microbiome data analysis, solving the technical limitations of the existing sequencing machines is required. Quality trimming is suggested to reduce the effect of the progressive decrease in sequencing quality with the increased length of the sequenced library. In this study, we examined the effect of the trimming thresholds (0-20 for QIIME1 and 0-30 for QIIME2) on the number of reads that remained after the quality control and chimera removal (the good reads). We also examined the distance of the analysis results to the gold standard using simulated samples. RESULTS: Quality trimming increased the number of good reads and abundance measurement accuracy in Illumina paired-end reads of the V3-V4 hypervariable region. CONCLUSIONS: Our results suggest that the pre-analysis trimming step should be included before the application of QIIME1 or QIIME2.

Compact, Automated, Inexpensive, and Field-Deployable Vacuum-Outlet Gas Chromatograph for Trace-Concentration Gas-Phase Organic Compounds.

The identification and quantification of gas-phase organic compounds, such as volatile organic compounds (VOCs), frequently use gas chromatography (GC), which typically requires high-purity compressed gases. We have developed a new instrument for trace-concentration measurements of VOCs and intermediate-volatility compounds of up to 14 carbon atoms in a fully automated (computer-free), independent, low-cost, compact GC-based system for the quantitative analysis of complex mixtures without the need for compressed, high-purity gases or expensive detectors. Through adsorptive analyte preconcentration, vacuum GC, photoionization detectors, and need-based water-vapor control, we enable sensitive and selective measurements with picogram-level limits of detection (i.e., under 15 ppt in a 4 L sample for most compounds). We validate performance against a commercial pressurized GC, including resolving challenging isomers of similar volatility, such as ethylbenzene and  m/ p-xylene. We employ vacuum GC across the whole column with filtered air as a carrier gas, producing long-term system stability and performance over a wide range of analytes. Through theory and experiments, we present variations in analyte diffusivities in the mobile phase, analyte elution temperatures, optimal linear velocities, and separation-plate heights with vacuum GC in air at different pressures, and we optimize our instrument to exploit these differences. At 2-6 psia, the molecular diffusion coefficients are 6.4-2.1 times larger and the elution temperatures are 39-92 °C lower than with pressurized GC with helium (at 30 psig) depending on the molecular structure, and we find a wide range of optimal linear velocities (up to 60 cm s-1) that are faster with broader tolerances than with pressurized-N2 GC.

Ultra-compact silicon photonics switch with high-density thermo-optic heaters.

Miniaturization of silicon photonics switches is essential for both dense integration and low-loss operation. However, it has remained unclear how small the switches can be made while using thermo-optic (TO) element switches. In this paper, the minimum possible distance between adjacent TO phase shifter arms was first examined. Next, the architecture for a switch matrix for the high-density arrangement of TO switches that includes multi-layer electrical wirings for compact electrical wire-out was proposed and demonstrated. As a result, we achieved 1/23 miniaturization of an 8 × 8 silicon photonics switch for the PIC part when compared with our previous design.

SiN/Si double-layer platform for ultralow-crosstalk multiport optical switches.

We experimentally demonstrate a double-layer platform of silicon nitride and silicon for ultralow-crosstalk multiport optical switches. By using a silicon nitride overpass with a large gap of 1.5 µm, we achieve a crosstalk of less than -50 dB and -45 dB almost entirely in the C-band for 4 × 4 and 16 × 16 switches, respectively. To demonstrate the scalability of the platform, we also measured a 32 × 32 passive test device and show that a worst-case crosstalk of less than -50 dB is feasible with appropriate gate switches.

Computational Model To Predict the Fraction of Unbound Drug in the Brain.

Knowing the value of the unbound drug fraction in the brain (fu,brain) is essential in estimating its effects and toxicity on the central nervous system (CNS); however, no model to predict fu,brain without experimental procedures is publicly available. In this study, we collected 253 measurements from the literature and an open database and built in silico models to predict fu,brain using only freely available software. By selecting appropriate descriptors, training, and evaluation, our model showed an acceptable performance on a test data set (R2 = 0.630, percentage of compounds predicted within a 3-fold error: 69.4%) using chemical structure alone. Our model is available at https://drumap.nibiohn.go.jp/fubrain/ , and all of our data sets can be obtained from the Supporting Information.

Integrated silicon photonic wavelength-selective switch using wavefront control waveguides.

A wavelength selective switch (WSS) can route optical signals into any of output ports by wavelength, and is a key component of the reconfigurable optical add/drop multiplexer. We propose a wavefront control type WSS using silicon photonics technology. This consists of several arrayed waveguide gratings sharing a large slab waveguide, wavefront control waveguides and distributed Bragg reflectors. The structure, design method, operating principle, and scalability of the WSS are described and discussed. We designed and fabricated a 1 × 2 wavefront control type WSS using silicon waveguides. This has 16 channels with a channel spacing of 200 GHz. The chip size is 5 mm × 10 mm. The switching operation was achieved by shifting the phase of the light propagating in each wavefront control waveguide, and by controlling the propagation direction in the shared large slab waveguide. Our WSS has no crossing waveguide, so the loss and the variation in loss between channels were small compared to conventional waveguide type WSSs. The heater power required for switching was 183 mW per channel, and the average extinction ratios routed to Output#1 and Output#2 were 9.8 dB and 10.2 dB, respectively.

Reconfigurable all-optical on-chip MIMO three-mode demultiplexing based on multi-plane light conversion.

We present, to the best of our knowledge, the first experimental demonstration of reconfigurable all-optical on-chip multi-input-multi-output three-mode demultiplexing based on multi-plane light conversion. The demultiplexer consists of cascaded phase shifter arrays and multimode interference couplers integrated on a compact silicon chip. By optimizing the phase shifters, reconfigurable three-mode demultiplexing is experimentally realized with wavelength-dependent loss of less than 3 dB and modal crosstalk of less than -10 dB over a 23 nm optical bandwidth. Error-free mode demultiplexing of 40 Gbps non-return-to-zero signal is also demonstrated.

Predicting Fraction Unbound in Human Plasma from Chemical Structure: Improved Accuracy in the Low Value Ranges.

Predicting the fraction unbound in plasma provides a good understanding of the pharmacokinetic properties of a drug to assist candidate selection in the early stages of drug discovery. It is also an effective tool to mitigate the risk of late-stage attrition and to optimize further screening. In this study, we built in silico prediction models of fraction unbound in human plasma with freely available software, aiming specifically to improve the accuracy in the low value ranges. We employed several machine learning techniques and built prediction models trained on the largest ever data set of 2738 experimental values. The classification model showed a high true positive rate of 0.826 for the low fraction unbound class on the test set. The strongly biased distribution of the fraction unbound in plasma was mitigated by a logarithmic transformation in the regression model, leading to improved accuracy at lower values. Overall, our models showed better performance than those of previously published methods, including commercial software. Our prediction tool can be used on its own or integrated into other pharmacokinetic modeling systems.

Non-duplicate polarization-diversity 8 × 8 Si-wire PILOSS switch integrated with polarization splitter-rotators.

We demonstrate a fully integrated polarization-diversity 8 × 8 thermo-optic Si-wire switch that uses only a single path-independent insertion loss (PILOSS) switch matrix. All input/output ports of the PILOSS switch matrix are uniquely assigned for polarization diversity without switch duplication. To integrate polarization splitter-rotators on a chip, we propose a compact path-length-equalized polarization-diversity switch configuration. Polarization-dependent loss (PDL) and differential group delay (DGD) are minimized. The 8 × 8 switch is fabricated by the CMOS-compatible fabrication process on 300-mm diameter wafer and additional etching of upper cladding after dicing. The chip size is 7 × 10.5 mm2. A PDL of 2 dB and a DGD of 1.5 ps are achieved. The crosstalk in the worst-case scenario is -20 dB in the full C-band.

Broadband silicon photonics 8 × 8 switch based on double-Mach-Zehnder element switches.

We fabricated and characterized a silicon photonics 8 × 8 strictly non-blocking optical switch based on double-Mach-Zehnder (MZ) element switches. The double-MZ switches, each of which consisted of an intersection and two asymmetric MZ switches, enabled the suppression of crosstalk across a wide wavelength range. The 8 × 8 switch exhibited an average fiber-to-fiber insertion loss of 11.2 dB and -20 dB crosstalk in a bandwidth wider than 30 nm. Furthermore, we constructed an 8 × 8 polarization-diversity switch by using two 8 × 8 switches and demonstrated 32-Gbaud dual-polarization, quadrature-phase-shift-keying, four-channel wavelength-division-multiplexed signal transmission without significant signal degradation.

Whole-exome sequencing and neurite outgrowth analysis in autism spectrum disorder.

Autism spectrum disorder (ASD) is a complex group of clinically heterogeneous neurodevelopmental disorders with unclear etiology and pathogenesis. Genetic studies have identified numerous candidate genetic variants, including de novo mutated ASD-associated genes; however, the function of these de novo mutated genes remains unclear despite extensive bioinformatics resources. Accordingly, it is not easy to assign priorities to numerous candidate ASD-associated genes for further biological analysis. Here we developed a convenient system for identifying an experimental evidence-based annotation of candidate ASD-associated genes. We performed trio-based whole-exome sequencing in 30 sporadic cases of ASD and identified 37 genes with de novo single-nucleotide variations (SNVs). Among them, 5 of those 37 genes, POGZ, PLEKHA4, PCNX, PRKD2 and HERC1, have been previously reported as genes with de novo SNVs in ASD; and consultation with in silico databases showed that only HERC1 might be involved in neural function. To examine whether the identified gene products are involved in neural functions, we performed small hairpin RNA-based assays using neuroblastoma cell lines to assess neurite development. Knockdown of 8 out of the 14 examined genes significantly decreased neurite development (P<0.05, one-way analysis of variance), which was significantly higher than the number expected from gene ontology databases (P=0.010, Fisher's exact test). Our screening system may be valuable for identifying the neural functions of candidate ASD-associated genes for further analysis and a substantial portion of these genes with de novo SNVs might have roles in neuronal systems, although further detailed analysis might eliminate false positive genes from identified candidate ASD genes.

Novel polarization diversity without switch duplication of a Si-wire PILOSS optical switch.

We demonstrate the compact polarization diversity based on the bidirectional full-port use of a path-independent-insertion-loss (PILOSS) optical switch. A polarization-diversity 4 × 4 strictly non-blocking optical switch is developed using a single thermooptic PILOSS Si-wire switch and fiber-based polarization beam splitters (PBSs) and combiners (PBCs). We measure characteristics of the switch and confirm that the proposed configuration demonstrates the performance in the insertion loss, polarization-dependent loss (PDL), and differential group delay (DGD) comparable with that of a conventional polarization-diversity 4 × 4 PILOSS switch using double switch elements. On the other hand, higher crosstalk is observed. The crosstalk increase is associated with the backward crosstalk at a waveguide intersection based on a directional coupler. The effect of the backward crosstalk on the total crosstalk is estimated, and future prospects are discussed.

Ultra-high-extinction-ratio 2 × 2 silicon optical switch with variable splitter.

We demonstrate a record-high extinction-ratio of 50.4 dB in a 2 × 2 silicon Mach-Zehnder switch equipped with a variable splitter as the front 3-dB splitter. The variable splitter is adjusted to compensate for the splitting-ratio mismatch between the front and rear 3-dB splitters. The high extinction ratio does not rely on waveguide crossings and meets a strong demand in applications to multiport circuit switches. Large fabrication tolerance will make the high extinction ratio compatible with a volume production with standard complementary metal-oxide semiconductor fabrication facilities.

Ultra-compact 32 × 32 strictly-non-blocking Si-wire optical switch with fan-out LGA interposer.

We demonstrate a 32 × 32 path-independent-insertion-loss optical path switch that integrates 1024 thermooptic Mach-Zehnder switches and 961 intersections on a small, 11 × 25 mm2 die. The switch is fabricated on a 300-mm-diameter silicon-on-insulator wafer by a complementary metal-oxide semiconductor-compatible process with advanced ArF immersion lithography. For reliable electrical packaging, the switch chip is flip-chip bonded to a ceramic interposer that arranges the electrodes in a 0.5-mm pitch land grid array. The on-chip loss is measured to be 15.8 ± 1.0 dB, and successful switching is demonstrated for digital-coherent 43-Gb/s QPSK signals. The total crosstalk of the switch is estimated to be less than -20 dB at the center wavelength of 1545 nm. The bandwidth narrowing caused by dimensional errors that arise during fabrication is discussed.

Tilted MMI crossings based on silicon wire waveguide.

Waveguide crossings employing tilted MMI structures on silicon wire waveguide are proposed and demonstrated. Intersecting angle of the two MMI waveguides is optimized for low crosstalk. The optimization is carried out with input polarizations specified. On the fabricated MMI crossings, crosstalk lower than -38 dB in the C-band was experimentally confirmed. A novel polarization-insensitive crossing based on a diversity circuit was fabricated. Crosstalk lower than -30 dB in the C-band is demonstrated.