Circadian rhythm and variability of large and small airway spirometric variables in healthy individuals.

Objective: To assess the diurnal rhythm and variability of lung function in healthy individuals, encompassing both large and small airways. Methods: A prospective study enrolled 35 healthy adults without a history of smoking. Initial spirometry and a bronchodilation test were performed using the Jaeger spirometer, followed by a seven-day continuous home monitoring using the GOSPT2000. We evaluated repeatability using the intraclass correlation coefficient and agreement through linear regression and Bland-Altman analyses. Circadian rhythm and variability in spirometric measurements were analyzed using the coefficient of variation (CV) and daily variation rate. Results: The GOSPT2000 demonstrated strong repeatability and high agreement with the Jaeger spirometer. Notable findings included a decrease in nocturnal forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and FEV3 by 44, 59, and 53 mL, respectively. In contrast, peak expiratory flow at noon showed an increase of 0.143L/min. Small-airway variables, including forced expiratory flow at 50% and 75% of the FVC and maximum midexpiratory flow, showed no significant diurnal variation. The nocturnal CV for large-airway variables was ≤ 4%, while for small-airway variables, it was ≤ 11.89%. Conclusion: This study has established a spectrum of variability for both large and small airways in healthy populations. The variability of small-airway variables is higher than that of large-airway variables. The investigation into the diurnal rhythms and variability characteristics of both large and small airway variables in the healthy population can serve as a foundation for diagnosing asthma or assessing the efficacy of asthma treatments.

Semaglutide combined with empagliflozin vs. monotherapy for non-alcoholic fatty liver disease in type 2 diabetes: Study protocol for a randomized clinical trial.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is strongly associated with type 2 diabetes mellitus (T2DM). Lifestyle intervention remains a preferred treatment modality for NAFLD. The glucagon-like peptide (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT-2) inhibitors have been developed as new glucose-lowering drugs, which can improve fatty liver via an insulin-independent glucose-lowering effect. However, studies exploring the efficacy of GLP-1 receptor agonists combined with SGLT-2 inhibitors in patients with NAFLD and T2DM are scanty. Thus, the present randomised controlled trial aims at comparing the efficacy and safety of semaglutide plus empagliflozin with each treatment alone in patients with NAFLD and T2DM. METHODS: This 52-week double-blinded, randomised, parallel-group, active-controlled trial evaluates the effects of semaglutide, empagliflozin and semaglutide + empagliflozin in 105 eligible overweight/obese subjects with NAFLD and T2DM. The primary outcome will be a change from baseline to week 52 in the controlled attenuation parameter, free fatty acid and glucagon. Secondary endpoints include changes in liver stiffness measurement, liver enzymes, blood glucose, lipid levels, renal function, electrolyte balances, minerals and bone metabolism, cytokines, high-sensitivity C-reactive protein, ferritin, anthropometric indicators, nonalcoholic fatty liver fibrosis score, fibrosis 4 score and homeostatic model assessment for insulin resistance. In addition, intention-to-treat, interim analysis and safety analysis will be performed. DISCUSSION: This double-blinded, randomised, clinical trial involves a multi-disciplinary approach and aims to explore the synergistic effects of the combination of semaglutide and empagliflozin. The results can provide important insights into mechanisms of GLP-1 receptor agonists and/or SGLT-2 inhibitors in patients with NAFLD and T2DM. TRIAL REGISTRATION: This study has been registered with Chinese Clinical Trial Registry (ChiCTR2300070674).

Arbitrary-ratio 1 × 2 optical power splitter based on thin-film lithium niobate.

Optical power splitters (OPSs) have been widely used in photonic integrated circuits, but an OPS with a large fabrication tolerance and free choice of power splitting ratio (PSR) is still highly desired for thin-film lithium niobate (TFLN) platform. Here, we propose and experimentally demonstrate several 1 × 2 OPSs with PSRs from 50:50 to 5:95 using TFLN platform. The proposed devices are built by multimode interference structure to achieve a broad bandwidth and large fabrication tolerance. Various PSRs can be obtained by adjusting the geometry structure of the multimode interference region. All of our fabricated devices feature an insertion loss lower than 0.3 dB at the wavelength of 1550 nm, and a PSR variation less than 3% in the range of 1520 nm to 1590 nm.

Increased NMDARs in neurons and glutamine synthetase in astrocytes underlying autistic-like behaviors of Gabrb1-/- mice.

Mutations of the GABA-A receptor subunit ß1 (GABRB1) gene are found in autism patients. However, it remains unclear how mutations in Gabrb1 may lead to autism. We generated Gabrb1-/- mouse model, which showed autistic-like behaviors. We carried out RNA-seq on the hippocampus and found glutamatergic pathway may be involved. We further carried out single-cell RNA sequencing on the whole brain followed by qRT-PCR, immunofluorescence, electrophysiology, and metabolite detection on specific cell types. We identified the up-regulated Glul/Slc38a3 in astrocytes, Grin1/Grin2b in neurons, glutamate, and the ratio of Glu/GABA in the hippocampus. Consistent with these results, increased NMDAR-currents and reduced GABAAR-currents in the CA1 neurons were detected in Gabrb1-/- mice. NMDAR antagonist memantine or Glul inhibitor methionine sulfoximine could rescue the abnormal behaviors in Gabrb1-/- mice. Our data reveal that upregulation of the glutamatergic synapse pathway, including NMDARs at neuronal synapses and glutamine exported by astrocytes, may lead to autistic-like behaviors.

Phase 1 clinical trial to assess safety and efficacy of NY-ESO-1-specific TCR T cells in HLA-A∗02:01 patients with advanced soft tissue sarcoma.

New York esophageal squamous cell carcinoma-1 (NY-ESO-1)-specific T cell receptor (TCR) T cell therapy is effective in tumors with NY-ESO-1 expression, but a safe and effective TCR-T cell therapeutic protocol remains to be improved. Here, we report a phase 1 investigational new drug clinical trial with TCR affinity-enhanced specific T cell therapy (TAEST16001) for targeting NY-ESO-1. Enrolled patients receive TAEST16001 cell infusion after dose-reduced lymphodepletion with cyclophosphamide (15 mg/kg/day × 3 days) combined with fludarabine (20 mg/m2/day × 3 days), and the TCR-T cells are maintained with low doses of interleukin-2 injection post-adoptive transfer. Analysis of 12 patients treated with the regimen demonstrates no treatment-related serious adverse events. The overall response rate is 41.7%. The median progression-free survival is 7.2 months, and the median duration of response is 13.1 months. The protocol of TAEST16001 cells delivers a safe and highly effective treatment for patients with advanced soft tissue sarcoma (ClinicalTrials.gov: NCT04318964).

CaZn(HPO3)2 and Ba2Zn(HPO3)3: novel alkaline-earth zincophosphites with diversified anionic frameworks.

Two novel alkaline-earth zincophosphites, namely CaZn(HPO3)2 and Ba2Zn(HPO3)3, were successfully synthesized under hydrothermal conditions. CaZn(HPO3)2 exhibits a three-dimensional (3D) anionic framework with a 6-connected uni-nodal pcu α-Po primitive cubic topology, constructed by unique Zn2O8 dimers and HPO3 pseudo-tetrahedra, while Ba2Zn(HPO3)3 displays one-dimensional (1D) [Zn(HPO3)3]4- anionic chains. It is worth mentioning that CaZn(HPO3)2 represents the first example of an alkaline-earth zincophosphite compound with a 3D framework structure. Our research also revealed the importance of both alkaline earth cation sizes and Zn/P ratios in anionic open-framework formation. The crystal structures of both compounds were further verified by energy dispersive spectroscopy, IR spectroscopy and Raman spectroscopy. Optical diffuse reflectance spectra, coupled with Tauc's fitting, revealed direct bandgaps with energy values of 4.33 and 4.48 eV for CaZn(HPO3)2 and Ba2Zn(HPO3)3, respectively, which differ from the prediction of theoretical calculations. Density of states calculations were conducted to reveal the origin of the bandgaps and bond interactions. Both compounds exhibited moderate birefringence values. This work may have implications for the design and synthesis of novel metal phosphites with desired properties.

MODILM: towards better complex diseases classification using a novel multi-omics data integration learning model.

BACKGROUND: Accurately classifying complex diseases is crucial for diagnosis and personalized treatment. Integrating multi-omics data has been demonstrated to enhance the accuracy of analyzing and classifying complex diseases. This can be attributed to the highly correlated nature of the data with various diseases, as well as the comprehensive and complementary information it provides. However, integrating multi-omics data for complex diseases is challenged by data characteristics such as high imbalance, scale variation, heterogeneity, and noise interference. These challenges further emphasize the importance of developing effective methods for multi-omics data integration. RESULTS: We proposed a novel multi-omics data learning model called MODILM, which integrates multiple omics data to improve the classification accuracy of complex diseases by obtaining more significant and complementary information from different single-omics data. Our approach includes four key steps: 1) constructing a similarity network for each omics data using the cosine similarity measure, 2) leveraging Graph Attention Networks to learn sample-specific and intra-association features from similarity networks for single-omics data, 3) using Multilayer Perceptron networks to map learned features to a new feature space, thereby strengthening and extracting high-level omics-specific features, and 4) fusing these high-level features using a View Correlation Discovery Network to learn cross-omics features in the label space, which results in unique class-level distinctiveness for complex diseases. To demonstrate the effectiveness of MODILM, we conducted experiments on six benchmark datasets consisting of miRNA expression, mRNA, and DNA methylation data. Our results show that MODILM outperforms state-of-the-art methods, effectively improving the accuracy of complex disease classification. CONCLUSIONS: Our MODILM provides a more competitive way to extract and integrate important and complementary information from multiple omics data, providing a very promising tool for supporting decision-making for clinical diagnosis.

Suicidal ideation in the general population in China after the COVID-19 pandemic was initially controlled.

BACKGROUND: The COVID-19 pandemic increases the risk of psychological problems including suicidal ideation (SI) in the general population. In this study, we investigated the risk factors of SI after the COVID-19 pandemic was initially controlled in China. METHODS: We conducted an online questionnaire via JD Health APP in China in June 2020. Demographic data, feelings and experiences related to the COVID-19 pandemic and psychological problems were collected. The participants (n = 14,690) were divided into the non-SI and SI groups. A binary logistic regression analysis was used to examine the correlates of SI. RESULTS: Nine percent of the participants (1328/14690) reported SI. The regression analysis showed that SI was positively associated with ethnic minority (OR = 1.42 [1.08-1.85]), age (e.g. 18-30 years: OR = 2.31 [1.67-3.20]), having history of mental disorders (OR = 2.75 [2.27-3.35]), daily life disturbance due to health problems (OR = 1.67 [1.38-2.01]), being around someone with the COVID-19 (OR = 1.58 [1.30-1.91]), being uncertain about effective disease control (OR = 1.23 [1.03-1.46]), and having depressive symptoms (OR = 4.40 [3.59-5.39]), insomnia symptoms (OR = 2.49 [2.13-2.90]) or psychological distress (OR = 1.87 [1.59-2.18]). LIMITATIONS: The main limitation is that the cross-sectional design of this study could not allow us to further explore the causality of SI. CONCLUSIONS: The prevalence of SI was relatively high in general population after the COVID-19 pandemic was initially controlled in China. SI should be monitored continually after the COVID-19 pandemic.

Modular Access to Chiral α-(Hetero)aryl Amines via Ni/Photoredox-Catalyzed Enantioselective Cross-Coupling.

Chiral α-aryl N-heterocycles are commonly found in natural products, pharmaceutical agents, and chiral catalysts but remain challenging to access via asymmetric catalysis. Herein, we report a general and modular approach for the direct enantioselective α-arylation of saturated azacycles and acyclic N-alkyl benzamides via nickel/photoredox dual catalysis. This process exploits the hydrogen atom transfer ability of photoeliminated chlorine radicals to convert azacycles to the corresponding α-amino alkyl radicals that then are coupled with ubiquitous and inexpensive (hetero)aryl chlorides. These coupling reactions require no oxidants or organometallic reagents, feature feedstock starting materials, a broad substrate scope, and high enantioselectivities, and are applicable to late-stage diversification of medicinally relevant complex molecules. Mechanistic studies suggest that the nickel catalyst uncommonly plays multiple roles, accomplishing chlorine radical generation, α-amino radical capture, cross-coupling, and asymmetric induction.

Compact substrate-removed thin-film lithium niobate electro-optic modulator featuring polarization-insensitive operation.

A compact polarization-insensitive electro-optic (EO) modulator, which allows the laser and modulator to be located at different locations while using a standard single-mode fiber to interconnect them, is highly desirable for 5G or future 6G wireless networks. Herein, we propose a modulator based on substrate-removed thin-film lithium niobate. The proposed device exhibits a polarization-dependent loss of 0.35 dB and on-chip loss of approximately 2 dB. The polarization insensitivity of the proposed device was experimentally demonstrated using a four-level pulse-amplitude modulation format at 50 Gbaud (100 Gb/ s).

High-performance polarization management devices based on thin-film lithium niobate.

High-speed polarization management is highly desirable for many applications, such as remote sensing, telecommunication, and medical diagnosis. However, most of the approaches for polarization management rely on bulky optical components that are slow to respond, cumbersome to use, and sometimes with high drive voltages. Here, we overcome these limitations by harnessing photonic integrated circuits based on thin-film lithium niobate platform. We successfully realize a portfolio of thin-film lithium niobate devices for essential polarization management functionalities, including arbitrary polarization generation, fast polarization measurement, polarization scrambling, and automatic polarization control. The present devices feature ultra-fast control speeds, low drive voltages, low optical losses and compact footprints. Using these devices, we achieve high fidelity polarization generation with a polarization extinction ratio up to 41.9 dB and fast polarization scrambling with a scrambling rate up to 65 Mrad s-1, both of which are best results in integrated optics. We also demonstrate the endless polarization state tracking operation in our devices. The demonstrated devices unlock a drastically new level of performance and scales in polarization management devices, leading to a paradigm shift in polarization management.

Relationships between the changes in sleep patterns and sleep quality among Chinese people during the 2019 coronavirus disease outbreak.

OBJECTIVE: Rapidly increasing numbers of confirmed cases and deaths during the 2019 coronavirus disease outbreak (COVID-19) resulted in widespread psychological problems in the Chinese population. The purpose of this study was to investigate the sleep quality and changes in sleep patterns before and during the outbreak in the general population in China and to determine factors related to sleep quality. METHODS: This cross-sectional study was conducted using an online questionnaire from 20 February to 29 February 2020 in China. Socio-demographic data, self-designed COVID-19-related characteristics, sleep patterns, and Pittsburgh Sleep Quality Index (PSQI) scores were obtained. Single factor analysis and multivariate binary logistic regression analysis were used. RESULTS: A total of 1897 individuals were included in our study, and 30.0% of participants reported suffering poor sleep quality (PSQI≥8). Logistic regression analysis found that the factors related to sleep quality included poor physical health (OR = 3.382, p < 0.001), respiratory disease (OR = 1.629, p = 0.008), other diseases (OR = 2.504, p = 0.012), suspected case of COVID-19 in the same community (OR = 1.928, p = 0.002), confirmed case of COVID-19 in the same community (OR = 2.183, p = 0.007), worry about being infected (OR = 2.336, p < 0.001), ≥1 h/day spent hearing COVID-19 information (OR = 1.960, p < 0.001), time difference in midpoint time in bed (OR = 1.230, p < 0.001), and time difference in time in bed (OR = 0.711, p < 0.001). CONCLUSIONS: Our study revealed that more than one-fourth of the participants suffered poor sleep quality during the COVID-19 outbreak. In addition to the poor health status and COVID-19-related anxiety, delayed sleep phase and reduced time in bed impacted sleep quality in the general population in China.

GEP-EpiSeeker: a gene expression programming-based method for epistatic interaction detection in genome-wide association studies.

BACKGROUND: Identification of epistatic interactions provides a systematic way for exploring associations among different single nucleotide polymorphism (SNP) and complex diseases. Although considerable progress has been made in epistasis detection, efficiently and accurately identifying epistatic interactions remains a challenge due to the intensive growth of measuring SNP combinations. RESULTS: In this work, we formulate the detection of epistatic interactions by a combinational optimization problem, and propose a novel evolutionary-based framework, called GEP-EpiSeeker, to detect epistatic interactions using Gene Expression Programming. In GEP-EpiSeeker, we propose several tailor-made chromosome rules to describe SNP combinations, and incorporate Bayesian network-based fitness evaluation into the evolution of tailor-made chromosomes to find suspected SNP combinations, and adopt the Chi-square test to identify optimal solutions from suspected SNP combinations. Moreover, to improve the convergence and accuracy of the algorithm, we design two genetic operators with multiple and adjacent mutations and an adaptive genetic manipulation method with fuzzy control to efficiently manipulate the evolution of tailor-made chromosomes. We compared GEP-EpiSeeker with state-of-the-art methods including BEAM, BOOST, AntEpiSeeker, MACOED, and EACO in terms of power, recall, precision and F1-score on the GWAS datasets of 12 DME disease models and 10 DNME disease models. Our experimental results show that GEP-EpiSeeker outperforms comparative methods. CONCLUSIONS: Here we presented a novel method named GEP-EpiSeeker, based on the Gene Expression Programming algorithm, to identify epistatic interactions in Genome-wide Association Studies. The results indicate that GEP-EpiSeeker could be a promising alternative to the existing methods in epistasis detection and will provide a new way for accurately identifying epistasis.

Genetic Contexts Characterize Dynamic Histone Modification Patterns Among Cell Types.

Histone modifications play critical roles in mammalian development, regulating chromatin structure and gene expression. Dynamic histone modifications among cell types have been shown to associate with changes in mammalian development. However, how to quantitatively measure the histone modification alterations and how histone modifications vary across cell types under different genetic contexts remain largely unexplored and whether these changes are related to the primary DNA sequence remains limited. Here, we employed an entropy-based method to measure histone modification alterations in six definite genomic regions across five cell types and identified lineage-specific histone modification genes. We observed that histone modification alterations prefer to enrich in 5'-UTR exons, and also in 3'-UTR exons and its downstream. Then we built a model to predict the histone modification patterns from the primary DNA sequence. We found that the frequencies of k-mer sequence compositions are predictive of histone modification patterns, suggesting that the primary DNA sequence correlated with the histone modification alterations among cell types. Additionally, the lineage-specific histone modification genes display a higher conservation and lower GC-content. Together, we performed a systematic analysis for histone modification alterations and demonstrated how to identify genomic region-specific elements of epigenetic and genetic regulation and histone modification patterns across different cell types.

Tunable asymmetric spin splitting by black phosphorus sandwiched epsilon-near-zero-metamaterial in the terahertz region.

In-plane photonic spin splitting effect is investigated in tunneling terahertz waves through an epsilon-near-zero metamaterial sandwiched between monolayer black phosphorus (BP). The strong in-plane anisotropy of BP layers will induce in-plane asymmetric spin splitting. The asymmetric spin splitting can be flexibly tuned by the angles between the incident plane and the armchair crystalline directions of the top and bottom BP layers, i.e., ϕ1 and ϕ2. Based on this, an angle-resolved barcode-encryption scheme is discussed. For the special case of ϕ1 = ϕ2 = 0 or 90°, the transmitted beam undergoes Goos-Hänchen shift, which varies with the carrier density of BP. We believe these findings can facilitate the development of novel optoelectronic devices in the Terahertz region.

Deletion of ligD significantly improves gene targeting frequency in the lignocellulolytic filamentous fungus Penicillium oxalicum.

To improve the gene targeting frequency (GTF) in the lignocellulolytic filamentous fungus Penicillium oxalicum HP7-1, the non-homologous end-joining (NHEJ) gene ligD was deleted. The obtained PoligD deletion mutant ΔPoligD showed no apparent defect in cellulase production, growth rate, and sensitivity towards osmotic stress and mutagen ethyl methanesulphonate (EMS), while increased sensitivity to high concentrations of methyl methanesulfonate (MMS). Deletion of PoligD gene resulted in significantly increased GTFs at three different loci in P. oxalicum, which are even higher than those in Poku70 deletion mutant. The GTF in ΔPoligD at PoargB (reached 97 %) and PoagaA (reached 90 %) loci increased 5.1- and 1.2-fold compared with that in wild-type strain (WT), while at the Podpp4 locus GTF was up to 27 % in ΔPoligD but close to 0 % in WT, with 0.5 kb homologous flanking regions. Furthermore, the argB and agaA nutritional selection in P. oxalicum was demonstrated and the PoargB and PoagaA genes could be used as selective markers in this fungus. Thus, the PoligD deletion mutant can be an important tool for the functional analysis of genes in P. oxalicum.

Identification of peptide-specific TCR genes by in vitro peptide stimulation and CDR3 length polymorphism analysis.

Identification of TCR genes specific for tumor-associated antigens (TAAs) is necessary for TCR gene modification of T cells, which is applied in anti-tumor adoptive T cell therapy (ACT). The usual identification methods are based on isolating single peptide-responding T cells and cloning the TCR gene by in vitro expansion or by single-cell RT-PCR. However, the long and exacting in vitro culture period and demanding operational requirements restrict the application of these methods. Immunoscope is an effective tool that profiles a repertoire of TCRs and identifies significantly expanded clones through CDR3 length analysis. In this study, a survivin-derived mutant peptide optimized for HLA-A2 binding was selected to load DCs and activate T cells. The monoclonal expansion of TCRA and TCRB genes was separately identified by Immunoscope analysis and following sequence identification, the properly paired TCR genes were transferred into T cells. Peptide recognition and cytotoxicity assays indicated that TCR-modified PBMCs could respond to both the mutant and wild type peptides and lyse target cells. These results show that combining Immunoscope with in vitro peptide stimulation provides an alternative and superior method for identifying specific TCR genes, which represents a significant advance for the application of TCR gene-modified T cells.

A protease-insensitive feruloyl esterase from China Holstein cow rumen metagenomic library: expression, characterization, and utilization in ferulic acid release from wheat straw.

A metagenomic library of China Holstein cow rumen microbes was constructed and screened for novel gene cluster. A novel feruloyl esterase (FAE) gene was identified with a length of 789 bp and encoded a protein displaying 56% identity to known esterase sequences. The gene was functionally expressed in Escherichia coli BL21 (DE3), and the total molecular weight of the recombined protein was 32.4 kDa. The purified enzyme showed a broad specificity against the four methyl esters of hydroxycinnamic acids and high activity (259.5 U/mg) to methyl ferulate at optimum conditions (pH 8.0, 40 °C). High thermal and pH stability were also observed. Moreover, the enzyme showed broad resistance to proteases. FAE-SH1 can enhance the release of ferulic acid from wheat straw with cellulase, ß-1,4-endoxylanase, ß-1,3-glucanase, and pectase. These features suggest FAE-SH1 as a good candidate to enhance biomass degradation and improve the health effects of food and forage.