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To identify risk genes whose expression are regulated by the reported risk variants and to explore the potential regulatory mechanism in schizophrenia (SCZ).
We systematically integrated three independent brain expression quantitative traits (eQTLs) (CommonMind, GTEx, and BrainSeq Phase 2, a total of 1039 individuals) and GWAS data (56 418 cases and 78 818 controls), with the use of transcriptome-wide association study (TWAS). Diffusion magnetic resonance imaging was utilized to quantify the integrity of white matter bundles and determine whether polygenic risk of novel genes linked to brain structure was present in patients with first-episode antipsychotic SCZ.
TWAS showed that eight risk genes (CORO7, DDAH2, DDHD2, ELAC2, GLT8D1, PCDHA8, THOC7, and TYW5) reached transcriptome-wide significance (TWS) level. These findings were confirmed by an independent integrative approach (i.e. Sherlock). We further conducted conditional analyses and identified the potential risk genes that driven the TWAS association signal in each locus. Gene expression analysis showed that several TWS genes (including CORO7, DDAH2, DDHD2, ELAC2, GLT8D1, THOC7 and TYW5) were dysregulated in the dorsolateral prefrontal cortex of SCZ cases compared with controls. TWS genes were mainly expressed on the surface of glutamatergic neurons, GABAergic neurons, and microglia. Finally, SCZ cases had a substantially greater TWS genes-based polygenic risk (PRS) compared to controls, and we showed that fractional anisotropy of the cingulum-hippocampus mediates the influence of TWS genes PRS on SCZ.
Our findings identified novel SCZ risk genes and highlighted the importance of the TWS genes in frontal-limbic dysfunctions in SCZ, indicating possible therapeutic targets.
OBJECTIVES/GOALS: The aims of this study were to: 1) determine the involvement of each Fc gamma receptor isoform in antibody-mediated crosslinking and internalization of LILRB4 in acute monocytic leukemia and 2) elucidate the role of this crosslinking and internalization in antibody-mediated immune regulation of these malignant cells. METHODS/STUDY POPULATION: To determine the involvement of Fc gamma receptors in antibody-mediated complex internalization, we generated acute monocytic leukemia cell lines with CRISPR-Cas9 knockout of each Fc gamma receptor isoform. We tested the effects of each knockout on anti-LILRB4 antibody-mediated internalization by flow cytometry and confirmed our findings with confocal microscopy. To elucidate the role of this crosslinking and internalization in immune regulation of acute monocytic leukemia, we conducted preliminary ELISA-based studies of the inflammatory signaling and cytokine release profiles of wild-type and Fc gamma receptor knockout cells treated with the LILRB4-targeting antibody. RESULTS/ANTICIPATED RESULTS: We have concluded that Fc gamma receptor I (CD64) plays a role in LILRB4 crosslinking and internalization by our anti-LILRB4 antibody and there are also contributions from Fc gamma receptor IIA (CD32A) observed in the absence of CD64 on the cell surface. Preliminary signaling studies have demonstrated that Fc gamma receptor-mediated antibody crosslinking and internalization of LILRB4 decreases anti-inflammatory signaling downstream of LILRB4 as well as pro-inflammatory signaling downstream of Fc gamma receptors, particularly in the absence of CD64 on the cell surface. The immunomodulatory effect of antibody-mediated LILRB4 crosslinking and internalization is being confirmed in follow-up signaling, cytokine release and lymphocyte activation studies. DISCUSSION/SIGNIFICANCE: This study will improve the efficacy of LILRB4-targeting antibody therapeutics for patients suffering from acute monocytic leukemia and help characterize CD64 and CD32A as potential clinical biomarkers for patients undergoing LILRB4-targeting antibody immunotherapeutic treatment, currently in first-in-human clinical trials.
Although aberrant brain regional responses are reported in social anxiety disorder (SAD), little is known about resting-state functional connectivity at the macroscale network level. This study aims to identify functional network abnormalities using a multivariate data-driven method in a relatively large and homogenous sample of SAD patients, and assess their potential diagnostic value.
Forty-six SAD patients and 52 demographically-matched healthy controls (HC) were recruited to undergo clinical evaluation and resting-state functional MRI scanning. We used group independent component analysis to characterize the functional architecture of brain resting-state networks (RSNs) and investigate between-group differences in intra-/inter-network functional network connectivity (FNC). Furtherly, we explored the associations of FNC abnormalities with clinical characteristics, and assessed their ability to discriminate SAD from HC using support vector machine analyses.
SAD patients showed widespread intra-network FNC abnormalities in the default mode network, the subcortical network and the perceptual system (i.e. sensorimotor, auditory and visual networks), and large-scale inter-network FNC abnormalities among those high-order and primary RSNs. Some aberrant FNC signatures were correlated to disease severity and duration, suggesting pathophysiological relevance. Furthermore, intrinsic FNC anomalies allowed individual classification of SAD v. HC with significant accuracy, indicating potential diagnostic efficacy.
SAD patients show distinct patterns of functional synchronization abnormalities both within and across large-scale RSNs, reflecting or causing a network imbalance of bottom-up response and top-down regulation in cognitive, emotional and sensory domains. Therefore, this could offer insights into the neurofunctional substrates of SAD.
The mitochondrial genome provides important information for phylogenetic analysis and an understanding of evolutionary origin. In this study, the mitochondrial genomes of Ilisha elongata and Setipinna tenuifilis were sequenced, which are typical circular vertebrate mitochondrial genomes composed of 16,770 and 16,805 bp, respectively. The mitogenomes of I. elongata and S. tenuifilis include 13 protein-coding genes (PCGs), 22 transfer RNA (tRNA), two ribosomal RNA (rRNA) genes and one control region (CR). Both two species' genome compositions were highly A + T biased and exhibited positive AT-skews and negative GC-skews. The genetic distance and Ka/Ks ratio analyses indicated that 13 PCGs were affected by purifying selection and the selection pressures were different from certain deep-sea fishes, which were most likely due to the difference in their living environment. Results of phylogenetic analysis support close relationships among Chirocentridae, Denticipitidae, Clupeidae, Engraulidae and Pristigasteridae based on the nucleotide and amino acid sequences of 13 PCGs. Within Clupeoidei, I. elongata and S. tenuifilis were most closely related to the family Pristigasteridae and Engraulidae, respectively. These results will help to better understand the evolutionary position of Clupeiformes and provide a reference for further phylogenetic research on Clupeiformes species.
O’Grady’s generalised Franchetta conjecture (GFC) is concerned with codimension 2 algebraic cycles on universal polarised K3 surfaces. In , this conjecture has been studied in the Betti cohomology groups. Following a suggestion of Voisin, we investigate this problem in the Deligne-Beilinson (DB) cohomology groups. In this paper, we develop the theory of Deligne-Beilinson cohomology groups on (smooth) Deligne-Mumford stacks. Using the automorphic cohomology group and Noether-Lefschetz theory, we compute the 4th DB-cohomology group of universal oriented polarised K3 surfaces with at worst an
-singularity and show that GFC for such family holds in DB-cohomology. In particular, this confirms O’Grady’s original conjecture in DB cohomology.
Persistent psychological distress associated with the coronavirus disease 2019 (COVID-19) pandemic has been well documented. This study aimed to identify pre-COVID brain functional connectome that predicts pandemic-related distress symptoms among young adults.
Baseline neuroimaging studies and assessment of general distress using the Depression, Anxiety and Stress Scale were performed with 100 healthy individuals prior to wide recognition of the health risks associated with the emergence of COVID-19. They were recontacted for the Impact of Event Scale-Revised and the Posttraumatic Stress Disorder Checklist in the period of community-level outbreaks, and for follow-up distress evaluation again 1 year later. We employed the network-based statistic approach to identify connectome that predicted the increase of distress based on 136-region-parcellation with assigned network membership. Predictive performance of connectome features and causal relations were examined by cross-validation and mediation analyses.
The connectome features that predicted emergence of distress after COVID contained 70 neural connections. Most within-network connections were located in the default mode network (DMN), and affective network-DMN and dorsal attention network-DMN links largely constituted between-network pairs. The hippocampus emerged as the most critical hub region. Predictive models of the connectome remained robust in cross-validation. Mediation analyses demonstrated that COVID-related posttraumatic stress partially explained the correlation of connectome to the development of general distress.
Brain functional connectome may fingerprint individuals with vulnerability to psychological distress associated with the COVID pandemic. Individuals with brain neuromarkers may benefit from the corresponding interventions to reduce the risk or severity of distress related to fear of COVID-related challenges.
Narrowband microwave generation with tuneable frequency is demonstrated by illuminating a photoconductive semiconductor switch (PCSS) with a burst-mode fibre laser. The whole system is composed of a high-power linearly polarized burst-mode pulsed fibre laser and a linear-state PCSS. To obtain a high-performance microwave signal, a desired envelope of burst is necessary and a pulse pre-compensation technique is adopted to avoid envelope distortion induced by the gain-saturation effect. Resulting from the technique, homogenous peak power distribution in each burst is ensured. The maximum energy of the laser burst pulse reaches 200 μJ with a burst duration of 100 ns at the average power of 10 W, corresponding to a peak power of 4 kW. When the PCSS is illuminated by the burst-mode fibre laser, narrowband microwave generation with tuneable frequency (0.80–1.12 GHz) is obtained with a power up to 300 W. To the best of the authors’ knowledge, it is the first demonstration of frequency-tuneable narrowband microwave generation based on a fibre laser. The high-power burst-mode fibre laser reported here has great potential for generating high-power arbitrary microwave signals for a great deal of applicable demands such as smart adaptive radar and intelligent high-power microwave systems.
Understanding the patterns of treatment response is critical for the treatment of patients with schizophrenia; one way to achieve this is through using a longitudinal dynamic process study design.
This study aims to explore the response trajectory of antipsychotics and compare the treatment responses of seven different antipsychotics over 6 weeks in patients with schizoprenia (trial registration: Chinese Clinical Trials Registry Identifier: ChiCTR-TRC-10000934).
Data were collected from a multicentre, randomised open-label clinical trial. Patients were evaluated with the Positive and Negative Syndrome Scale (PANSS) at baseline and follow-up at weeks 2, 4 and 6. Trajectory groups were classified by the method of k-means cluster modelling for longitudinal data. Trajectory analyses were also employed for the seven antipsychotic groups.
The early treatment response trajectories were classified into a high-trajectory group of better responders and a low-trajectory group of worse responders. The results of trajectory analysis showed differences compared with the classification method characterised by a 50% reduction in PANSS scores at week 6. A total of 349 patients were inconsistently grouped by the two methods, with a significant difference in the composition ratio of treatment response groups using these two methods (χ2 = 43.37, P < 0.001). There was no differential contribution of high- and low trajectories to different drugs (χ2 = 12.52, P = 0.051); olanzapine and risperidone, which had a larger proportion in the >50% reduction at week 6, performed better than aripiprazole, quetiapine, ziprasidone and perphenazine.
The trajectory analysis of treatment response to schizophrenia revealed two distinct trajectories. Comparing the treatment responses to different antipsychotics through longitudinal analysis may offer a new perspective for evaluating antipsychotics.
Gust/turbulence–leading edge interaction is a significant source of airfoil broadband noise. An approach often used to predict the sound is based on Amiet’s flat-plate solution. Analytical studies have been conducted to investigate the influences of airfoil geometries, non-uniform mean flows and turbulence statistics, which, however, were often too convoluted. In this work, the problem is revisited by proposing simple corrections to the standard flat-plate solution to account for the effect of non-uniform mean flows of real airfoils. A key step in the method is to use a new space–time transformation that is analogous to the Prandtl–Glauert transformation to simplify the sound governing equation with spatially varying coefficients to a classical wave equation, which is then solved using the Schwarzschild technique as in Amiet’s solution. The impacts of Mach number, wavenumber and airfoil geometry on the prediction accuracy are investigated for both single-frequency and broadband cases, and the results are compared against high-fidelity simulations. It predicts the sound reduction by the airfoil thickness, and reveals that the reduction is caused by the non-uniform streamwise velocity. The limitations of the model are discussed and the approximation errors are estimated. In general, the prediction error increases with the airfoil thickness, the sound frequency and the flow Mach number. Nevertheless, in all cases studied in this work, the proposed correction can effectively improve the prediction accuracy of the flat-plate solution much more efficiently compared to numerical solutions of the Euler equations using computational aeroacoustics.
Emergency department (ED) crowding is associated with increased morbidity and mortality. Its etiology is multifactorial, and frequent ED use (defined as more or equal to five visits per year) is a major contributor to high patient volumes. Our primary objective is to characterize the frequent user population. Our secondary objective is to examine risk factors for frequent emergency use.
We conducted a retrospective cohort study of pediatric emergency department (PED) visits at the Montreal Children’s Hospital using the Système Informatique Urgence (SIURGE), electronic medical record database. We analysed the relation between patient’s characteristics and the number of PED visits over a 1-year period following the index visit.
Patients totalling 52,088 accounted for 94,155 visits. Of those, 2,474 (4.7%) patients had five and more recurrent visits and accounted for 16.6% (15,612 visits) of the total PED visits. Lower level of acuity at index visit (odds ratio [OR] 0.85) was associated with a lower number of recurrent visits. Lower socioeconomic status (social deprivation index OR 1.09, material deprivation index OR 1.08) was associated with a higher number of recurrent visits. Asthma (OR 1.57); infectious ear, nose, and sinus disorders (OR 1.33); and other respiratory disorders (OR 1.56) were independently associated with a higher incidence of a recurrent visit within the year following the first visit.
Our study is the first Canadian study to assess risk factors of frequent pediatric emergency use. The identified risk factors and diagnoses highlight the need for future evidence-based, targeted innovative research evaluating strategies to minimize ED crowding, to improve health outcomes and to improve patient satisfaction.
The Qiangtang Metamorphic Belt (QMB) was considered to have either formed in situ by amalgmation of the North and South Qiangtang blocks or been underthrust from the Jinsha suture and exhumed in the interior of a single ‘Qiangtang Block’. A new Sphaeroschwagerina fusuline fauna discovered in the Raggyorcaka Lake area supports the interpretation that the North and South Qiangtang blocks were separated by a wide ocean during Asselian (Early Permian) time, indicating that the QMB was formed by the suturing of the Palaeotethys Ocean along the Longmu Co-Shuanghu suture.
The mitochondrial genome is maternally inherited in animals, despite the fact that paternal mitochondria enter oocytes during fertilization. Autophagy and ubiquitin-mediated degradation are responsible for the elimination of paternal mitochondria in Caenorhabditis elegans; however, the involvement of these two processes in the degradation of paternal mitochondria in mammals is not well understood. We investigated the localization patterns of light chain 3 (LC3) and ubiquitin in mouse and porcine embryos during preimplantation development. We found that LC3 and ubiquitin localized to the spermatozoon midpiece at 3 h post-fertilization, and that both proteins were colocalized with paternal mitochondria and removed upon fertilization during the 4-cell stage in mouse and the zygote stage in porcine embryos. Sporadic paternal mitochondria were present beyond the morula stage in the mouse, and paternal mitochondria were restricted to one blastomere of 4-cell embryos. An autophagy inhibitor, 3-methyladenine (3-MA), did not affect the distribution of paternal mitochondria compared with the positive control, while an autophagy inducer, rapamycin, accelerated the removal of paternal mitochondria compared with the control. After the intracytoplasmic injection of intact spermatozoon into mouse oocytes, LC3 and ubiquitin localized to the spermatozoon midpiece, but remnants of undegraded paternal mitochondria were retained until the blastocyst stage. Our results show that paternal mitochondria colocalize with autophagy receptors and ubiquitin and are removed after in vitro fertilization, but some remnants of sperm mitochondrial sheath may persist up to morula stage after intracytoplasmic spermatozoon injection (ICSI).
Confocal Raman microspectroscopy (CRM) has emerged as a powerful approach to visualize the compositional distribution in lignocellulosic biomass of cell walls. In this work, the applicability of CRM for imaging the topochemical correlation between lignin and hydroxycinnamic acids (HCA) in the Miscanthus sinensis internode was explored. Model compound [p-coumaric acid (PCA) and ferulic acid (FA)] analysis indicated that the band region from 1,152 to 1,197 cm−1 can be used to characterize the distribution of HCA. Raman images calculated by integrating over the area intensity of characteristic spectral regions showed heterogeneous distribution of lignin and HCA at cellular and sub-cellular level. When overlaying the Raman image of lignin and HCA distribution, it was found that these two polymers were co-located in the middle lamella and secondary wall of corresponding cells. Raman images for the band intensity ratio (1,173 cm−1/1,603 cm−1) indicated a clear association between lignin and HCA distribution within morphologically distinct cell wall layers of sclerenchyma fibers and the parenchyma. This is the first time that the spatial correlation between lignin and HCA concentration has been illustrated by a microspectroscopy imaging approach. The results are of importance in extending the current understanding of lignin and aromatics topochemistry in herbaceous biomass.
The aim of the present study was to evaluate the effects of lutein and lycopene supplementation on carotid artery intima–media thickness (CAIMT) in subjects with subclinical atherosclerosis. A total of 144 subjects aged 45–68 years were recruited from local communities. All the subjects were randomly assigned to receive 20 mg lutein/d (n 48), 20 mg lutein/d+20 mg lycopene/d (n 48) or placebo (n 48) for 12 months. CAIMT was measured using Doppler ultrasonography at baseline and after 12 months, and serum lutein and lycopene concentrations were determined using HPLC. Serum lutein concentrations increased significantly from 0·34 to 1·96 μmol/l in the lutein group (P< 0·001) and from 0·35 to 1·66 μmol/l in the combination group (P< 0·001). Similarly, serum lycopene concentrations increased significantly from 0·18 to 0·71 μmol/l in the combination group at month 12 (P< 0·001), whereas no significant change was observed in the placebo group. The mean values of CAIMT decreased significantly by 0·035 mm (P= 0·042) and 0·073 mm (P< 0·001) in the lutein and combination groups at month 12, respectively. The change in CAIMT was inversely associated with the increase in serum lutein concentrations (P< 0·05) in both the active treatment groups and with that in serum lycopene concentrations (β = − 0·342, P= 0·031) in the combination group. Lutein and lycopene supplementation significantly increased the serum concentrations of lutein and lycopene with a decrease in CAIMT being associated with both concentrations. In addition, the combination of lutein and lycopene supplementation was more effective than lutein alone for protection against the development of CAIMT in Chinese subjects with subclinical atherosclerosis, and further studies are needed to confirm whether synergistic effects of lutein and lycopene exist.
Red-emitting phosphor of Ca0.8Zn0.2TiO3:0.2 mol% Pr3+ was synthesized by the hydrothermal method with urea as a mineralizer. The crystalline structure, micromorphology, and luminescent properties of the resultant phosphor were investigated. Results show that elevated calcination temperature does not change the shape of particles that are hollow spheres with a shell thickness of 210–480 nm, and smaller particles are in the middle of the larger ones. The emission intensity at 612 nm originated from 1D2 → 3H4 transition of Pr3+ ions increases with the elevated calcination temperature due to a higher crystallinity. Excitation curves consist of two strong broad bands centered at about 330 and 380 nm and a weaker broad band range from 450 to 500 nm. The sample prepared by the hydrothermal method has better luminescent properties than that of its counterpart prepared by the solid-state method, especially the improvement of near-UV region (380 nm) excitation intensity.
The AlGaN/GaN/InGaN/GaN double heterojunction high electron mobility transistors (DH-HEMTs) sample has been grown by MOCVD on (0 0 0 1) sapphire substrate. The structure features a 7 nm In0.046Ga0.954N interlayer determined by Rutherford backscattering (RBS). Since the polarization field in the InGaN interlayer is opposite to it in the AlGaN layer, an additional potential barrier is introduced between the two-dimensional electron gas (2DEG) channel and buffer, leading to enhanced carrier confinement and improved buffer isolation. The GaN layers between the AlGaN layer and InGaN interlayer are divided into two layers consisting of GaN channel layer which provides high mobility 2DEG grown at 1070 °C and GaN spacer layer grown at the same temperature as InGaN interlayer (800 °C) to prevent indium diffusion. RBS measurement confirms that the 3 nm GaN spacer layer isolates the InGaN interlayer well and free from diffusion. Hall measurement has been performed, the mobility as high as 1552 cm2/V s at room temperature is obtained and the sheet carrier density is 1.55 × 1013 cm−2. The average sheet resistance is 331 Ω/sq, respectively. The mobility obtained in this paper is about 20% higher than similar structures reported.
The driving mechanism of solar flares and coronal mass ejections is a topic of ongoing debate, apart from the consensus that magnetic reconnection plays a key role during the impulsive process. While present solar research mostly depends on observations and theoretical models, laboratory experiments based on high-energy density facilities provide the third method for quantitatively comparing astrophysical observations and models with data achieved in experimental settings. In this article, we show laboratory modeling of solar flares and coronal mass ejections by constructing the magnetic reconnection system with two mutually approaching laser-produced plasmas circumfused of self-generated megagauss magnetic fields. Due to the Euler similarity between the laboratory and solar plasma systems, the present experiments demonstrate the morphological reproduction of flares and coronal mass ejections in solar observations in a scaled sense, and confirm the theory and model predictions about the current-sheet-born anomalous plasmoid as the initial stage of coronal mass ejections, and the behavior of moving-away plasmoid stretching the primary reconnected field lines into a secondary current sheet conjoined with two bright ridges identified as solar flares.
We report the fabrication of AlGaN/GaN high electron mobility transistors (MIS-HEMTs) with a high breakdown voltage by employing a metal-insulator-semiconductor (MIS) gate structure using Si3N4 insulator. The Si3N4 films were deposited by plasma enhanced chemical vapor deposition (PECVD) as the surface passivation, interlayer films and the gate dielectric. In comparison with Schottky-gate HEMTs, the gate leakage currents of MIS-HEMTs exhibited three orders of magnitude reduction. With similar device structures, the off-state breakdown voltage of MIS-HEMTs was 1050 V with a specific on-resistance of 4.0 mΩ cm2, whereas the breakdown voltage and specific on-resistance of SG-HEMTs were 740 V and 4.4 mΩ cm2, respectively. In addition, the MIS-HEMTs exhibited little current slump in the pulsed measurements and possessed faster switch speed than Si MOSFET. We demonstrate that AlGaN/GaN MIS-HEMTs are promising not only for microwave applications but also for high power switching applications.
A useful procedure is described to rapidly obtain Bragg-reflection intensities from the FULLPROF suite, and the Bragg intensities can then be input into the GEST and the PECKCRYST programs for crystal-structure determination of small molecules. An example on using the new procedure for the structure determination from powder diffraction determination of hydrochlorothiazide (C7H8ClN3O4S2) is presented, and the powder-structure results obtained by the PECKCRYST program are in good agreement with previously reported single-crystal results.