SUMMIT-FA: a new resource for improved transcriptome imputation using functional annotations.

Transcriptome-wide association studies (TWAS) integrate gene expression prediction models and genome-wide association studies (GWAS) to identify gene-trait associations. The power of TWAS is determined by the sample size of GWAS and the accuracy of the expression prediction model. Here, we present a new method, the Summary-level Unified Method for Modeling Integrated Transcriptome using Functional Annotations (SUMMIT-FA), which improves gene expression prediction accuracy by leveraging functional annotation resources and a large expression quantitative trait loci (eQTL) summary-level dataset. We build gene expression prediction models in whole blood using SUMMIT-FA with the comprehensive functional database MACIE and eQTL summary-level data from the eQTLGen consortium. We apply these models to GWAS for 24 complex traits and show that SUMMIT-FA identifies significantly more gene-trait associations and improves predictive power for identifying "silver standard" genes compared to several benchmark methods. We further conduct a simulation study to demonstrate the effectiveness of SUMMIT-FA.

Structural basis of peptidomimetic agonism revealed by small- molecule GLP-1R agonists Boc5 and WB4-24.

Glucagon-like peptide-1 receptor (GLP-1R) agonists are effective in treating type 2 diabetes and obesity with proven cardiovascular benefits. However, most of these agonists are peptides and require subcutaneous injection except for orally available semaglutide. Boc5 was identified as the first orthosteric nonpeptidic agonist of GLP-1R that mimics a broad spectrum of bioactivities of GLP-1 in vitro and in vivo. Here, we report the cryoelectron microscopy structures of Boc5 and its analog WB4-24 in complex with the human GLP-1R and Gs protein. Bound to the extracellular domain, extracellular loop 2, and transmembrane (TM) helices 1, 2, 3, and 7, one arm of both compounds was inserted deeply into the bottom of the orthosteric binding pocket that is usually accessible by peptidic agonists, thereby partially overlapping with the residues A8 to D15 in GLP-1. The other three arms, meanwhile, extended to the TM1-TM7, TM1-TM2, and TM2-TM3 clefts, showing an interaction feature substantially similar to the previously known small-molecule agonist LY3502970. Such a unique binding mode creates a distinct conformation that confers both peptidomimetic agonism and biased signaling induced by nonpeptidic modulators at GLP-1R. Further, the conformational difference between Boc5 and WB4-24, two closed related compounds, provides a structural framework for fine-tuning of pharmacological efficacy in the development of future small-molecule therapeutics targeting GLP-1R.

Antimony Redox Catalysis: Hydroboration of Disulfides through Unique Sb(I)/Sb(III) Redox Cycling.

The stibinidene ArSbI (Ar = [2,6-(tBuN═CH)2-C6H3], 1) reacts with S2Tol2 (Tol = p-tolyl) to form ArSbIII(STol)2 (2), which upon treatment with pinacolborane, regenerates 1. These processes unveil an unprecedented antimony redox catalysis involving Sb(I)/Sb(III) cycling for the hydroboration of organic disulfides. Elementary reaction studies and density functional theory calculations support that the catalysis mimics transition metal processes, proceeding through oxidative addition, ligand metathesis, and reductive elimination. The thiophenols and sulfidoborates generated from the hydroboration of disulfides react in situ with α,ß-unsaturated carbonyl compounds with the assistance of 1 as a base catalyst. These tandem reactions establish a one-pot synthetic method for ß-sulfido carbonyl compounds, in which a stibinidene functions as a redox catalyst and a base catalyst successively, illustrating the versatility and efficiency of antimony catalysis in organic synthesis.

Modulation of Electrokinetic Potentials Using Graphene-Based Surfaces and Variable Substrate Charge Density.

Enhanced electrokinetic phenomena, manifested through the observation of a large streaming potential (Vs), were obtained in microchannels with single-layer graphene (SLG)-coated and few-layer graphene (FLG)-coated surfaces. In comparison to silicon microchannels, the Vs obtained for a given pressure difference along the channel (ΔP) was higher by 75% for the graphene-based channels, with larger values in the SLG case. Computational modeling was used to correlate the surface charge density, tuned through plasma processing, and related zeta potential to measured Vs. The implications related to deploying lower dimensional material surfaces for modulating electrokinetic flows were investigated.

Green space and its types can attenuate the associations of PM2.5 and its components with prediabetes and diabetes-- a multicenter cross-sectional study from eastern China.

BACKGROUND: The effect of fine particulate matter (PM2.5) components on prediabetes and diabetes is of concern, but the evidence is limited and the specific role of different green space types remains unclear. This study aims to investigate the relationship of PM2.5 and its components with prediabetes and diabetes as well as the potential health benefits of different types and combinations of green spaces. METHODS: A multicenter cross-sectional study was conducted in eastern China by using a multi-stage random sampling method. Health screening and questionnaires for 98,091 participants were performed during 2017-2020. PM2.5 and its five components were estimated by the inverse distance weighted method, and green space was reflected by the Normalized Difference Vegetation Index (NDVI), percentages of tree or grass cover. Multivariate logistic regression and quantile g-computing were used to explore the associations of PM2.5 and five components with prediabetes and diabetes and to elucidate the potential moderating role of green space and corresponding type combinations in these associations. RESULTS: Each interquartile range (IQR) increment of PM2.5 was associated with both prediabetes (odds ratio [OR]: 1.15, 95%CI [confidence interval]: 1.10-1.20) and diabetes (OR: 1.18, 95% CI: 1.11-1.25), respectively. All five components of PM2.5 were related to prediabetes and diabetes. The ORs of PM2.5 on diabetes were 1.49 (1.35-1.63) in the low tree group and 0.90 (0.82-0.98) in the high tree group, respectively. In the high tree-high grass group, the harmful impacts of PM2.5 and five components were significantly lower than in the other groups. CONCLUSION: Our study suggested that PM2.5 and its components were associated with the increased risk of prediabetes and diabetes, which could be diminished by green space. Furthermore, the coexistence of high levels of tree and grass cover provided greater benefits. These findings had critical implications for diabetes prevention and green space-based planning for healthy city.

A qualitative study on inner experience of self-management behavior among elderly patients with type 2 diabetes in rural areas.

BACKGROUND: As a chronic metabolic disease, diabetes poses a serious threat to human health and has become a major public health problem in China and worldwide. In 2020, 30% of Chinese people (aged ≥ 60 years) reported having diabetes mellitus. Moreover, individuals with diabetes living in rural areas face a significantly higher mortality risk compared to those in urban areas. In this study, we explored the inner experience of self-management behaviors in elderly patients with type 2 diabetes in rural areas to inform targeted interventions. METHODS: A phenomenological research design was used to explore the inner experience of self-management in rural elderly diabetes. Ten elderly diabetic patients were sampled from December 2022 to March 2023 in rural areas of Yangcheng County, Jincheng City, ShanXi Province, China. The seven-step Colaizzi phenomenological was used to analyze the interview data and generate themes. RESULTS: Four themes emerged: "Insufficient self-management cognition", "Negative self-management attitude", "Slack self-management behavior", and "No time for self-management". CONCLUSION: The level of self-management among elderly patients with type 2 diabetes in rural areas is low. Healthcare professionals should develop targeted interventions aimed at enhancing their cognitive levels, modifying their coping styles, and improving their self-management abilities to improve their quality of life.

Splicing transcriptome-wide association study to identify splicing events for pancreatic cancer risk.

A large proportion of the heritability of pancreatic cancer risk remains elusive, and the contribution of specific mRNA splicing events to pancreatic cancer susceptibility has not been systematically evaluated. In this study, we performed a large splicing transcriptome-wide association study (spTWAS) using three modeling strategies (Enet, LASSO and MCP) to develop alternative splicing genetic prediction models for identifying novel susceptibility loci and splicing introns for pancreatic cancer risk by assessing 8275 pancreatic cancer cases and 6723 controls of European ancestry. Data from 305 subjects of whom the majority are of European descent in the Genotype-Tissue Expression Project (GTEx) were used and both cis-acting and promoter-enhancer interaction regions were considered to build these models. We identified nine splicing events of seven genes (ABO, UQCRC1, STARD3, ETAA1, CELA3B, LGR4 and SFT2D1) that showed an association of genetically predicted expression with pancreatic cancer risk at a false discovery rate ≤0.05. Of these genes, UQCRC1 and LGR4 have not yet been reported to be associated with pancreatic cancer risk. Fine-mapping analyses supported likely causal associations corresponding to six splicing events of three genes (P4HTM, ABO and PGAP3). Our study identified novel genes and splicing events associated with pancreatic cancer risk, which can improve our understanding of the etiology of this deadly malignancy.

A splicing transcriptome-wide association study identifies novel altered splicing for Alzheimer's disease susceptibility.

Alzheimer's disease (AD) is a common neurodegenerative disease in aging individuals. Alternative splicing is reported to be relevant to AD development while their roles in etiology of AD remain largely elusive. We performed a comprehensive splicing transcriptome-wide association study (spTWAS) using intronic excision expression genetic prediction models of 12 brain tissues developed through three modelling strategies, to identify candidate susceptibility splicing introns for AD risk. A total of 111,326 (46,828 proxy) cases and 677,663 controls of European ancestry were studied. We identified 343 associations of 233 splicing introns (143 genes) with AD risk after Bonferroni correction (0.05/136,884 = 3.65 × 10-7). Fine-mapping analyses supported 155 likely causal associations corresponding to 83 splicing introns of 55 genes. Eighteen causal splicing introns of 15 novel genes (EIF2D, WDR33, SAP130, BYSL, EPHB6, MRPL43, VEGFB, PPP1R13B, TLN2, CLUHP3, LRRC37A4P, CRHR1, LINC02210, ZNF45-AS1, and XPNPEP3) were identified for the first time to be related to AD susceptibility. Our study identified novel genes and splicing introns associated with AD risk, which can improve our understanding of the etiology of AD.

Rapid detection of hydrogen using narrow bandwidth fiber-optic spectral combs with a low limit of detection.

The all-fiber detection solutions are the key technology to detecting hydrogen leakage in time because of the low explosive limit of the hydrogen-air mixture gas. However, most of the fiber-optic-based hydrogen sensing platforms must disrupt their structure to achieve a special architecture for interacting with the hydrogen. Here, we report a promising non-damaged structure of fiber-optic narrow bandwidth spectral combs, that can be developed to determine the refractive change as low as 10-5 using its cut-off cladding resonance mode. Such high performance of response for the refractive index induces a rapid detection of hydrogen after a proper thickness of palladium was deposited on the device. An average response time of hydrogen of 4 min with a low limit of detection of 348 ppm was achieved. It is demonstrated that these narrow bandwidth fiber-optic resonance combs can be used for gas detection after being combined with functional materials.

Ultra-compact and ultra-broadband arbitrary-order silicon photonic multi-mode converter designed by an intelligent algorithm.

Multi-mode converters, which can achieve spatial mode conversion in multimode waveguide, play a key role in multi-mode photonics and mode-division multiplexing (MDM). However, rapid design of high-performance mode converters with ultra-compact footprint and ultra-broadband operation bandwidth is still a challenge. In this work, through combining adaptive genetic algorithm (AGA) and finite element simulations, we present an intelligent inverse design algorithm and successfully designed a set of arbitrary-order mode converters with low excess losses (ELs) and low crosstalk (CT). At the communication wavelength of 1550 nm, the footprint of designed TE0-n (n = 1, 2, 3, 4) and TE2-n (n = 0, 1, 3, 4) mode converters are only 1.8 × 2.2 µm2. The maximum and minimum conversion efficiency (CE) is 94.5% and 64.2%, and the maximum and minimum ELs/CT are 1.92/-10.9 dB and 0.24/-20 dB, respectively. Theoretically, the smallest bandwidth for simultaneously achieving ELs ≤ 3 dB and CT ≤ -10 dB exceeds 70 nm, which can be as large as 400 nm for the case of low-order mode conversion. Moreover, the mode converter in conjunction with a waveguide bend allows for mode-conversion in ultra-sharp waveguide bends, significantly increasing the density of on-chip photonic integration. This work provides a general platform for the realization of mode converters and has good prospect in application of multimode silicon photonics and MDM.

All-silicon polarization-independent broadband achromatic metalens designed for the mid-wave and long-wave infrared.

Metasurfaces demonstrate excellent capabilities in manipulating the phase, amplitude and polarization of light. Metalens, as a typical kind of metasurface devices, shows great prospect in simplifying imaging systems. However, like diffractive optical elements, intrinsic dispersion of metasurfaces is high. Thus, significant chromatic aberration is present in common metalenses, deteriorating imaging quality under broadband illumination condition and limiting their applications. To tackle this problem, broadband achromatic metalenses have been proposed and demonstrated in the visible and near-infrared wavelength regions so far. However, broadband achromatic metalens working in the mid-wave and long-wave infrared is still rare. In this paper, thanks to the ingenious design of meta-units that provide the required local phase and phase dispersion, several all-silicon broadband achromatic metalenses working in the mid-wave infrared (3-5 µm) or long-wave infrared (8-14 µm) wavelengths are proposed. Numerical simulation results demonstrate that the designed broadband achromatic metalenses can provide a near-constant focal length with small deviations and an average focusing efficiency of about 70% over the whole operation bandwidths. In addition, these metalenses hold near diffraction-limited focusing capability and polarization-independent focusing features. The achromatic metalenses proposed here are beneficial for improving imaging quality under broadband illumination and increasing detection efficiency of mid-wave and long-wave infrared detection systems.

Dynamic tripartite construct of interregional engram circuits underlies forgetting of extinction memory.

Fear extinction allows for adaptive control of learned fear responses but often fails, resulting in a renewal or spontaneous recovery of the extinguished fear, i.e., forgetting of the extinction memory readily occurs. Using an activity-dependent neuronal labeling strategy, we demonstrate that engram neurons for fear extinction memory are dynamically positioned in the medial prefrontal cortex (mPFC), basolateral amygdala (BLA), and ventral hippocampus (vHPC), which constitute an engram construct in the term of directional engram synaptic connectivity from the BLA or vHPC to mPFC, but not that in the opposite direction, for retrieval of extinction memory. Fear renewal or spontaneous recovery switches the extinction engram construct from an accessible to inaccessible state, whereas additional extinction learning or optogenetic induction of long-term potentiation restores the directional engram connectivity and prevents the return of fear. Thus, the plasticity of engram construct underlies forgetting of extinction memory.

Influence of Five Drying Methods on Active Compound Contents and Bioactivities of Fresh Flowers from Syringa pubescens Turcz.

The flower of Syringa pubescens Turcz. is used in Chinese folk medicine and also as a flower tea for healthcare. The effects of five drying methods on the active compound contents, the antioxidant abilities, anti-inflammatory properties and enzyme inhibitory activities were evaluated. The plant materials were treated using shade-drying, microwave-drying, sun-drying, infrared-drying and oven-drying. The seven active compounds were simultaneously determined using an HPLC method. Furthermore, the chemical profile was assessed using scanning electron microscopy, ultraviolet spectroscopy and infrared spectroscopy. The antioxidant capacities and protective effects on L02 cells induced with hydrogen peroxide were measured. The anti-inflammatory effects on lipopolysaccharide-induced RAW264.7 cells were investigated. The enzyme inhibitory activities were determined against α-amylase, α-glucosidase cholinesterases and tyrosinase. The results indicated that drying methods had significant influences on the active compound contents and biological properties. Compared with other samples, the OD samples possessed low IC50 values with 0.118 ± 0.004 mg/mL for DPPH radical, 1.538 ± 0.0972 for hydroxyl radical and 0.886 ± 0.199 mg/mL for superoxide radical, while the SHD samples had stronger reducing power compared with other samples. The SHD samples could be effective against H2O2-induced injury on L02 cells by the promoting of T-AOC, GSH-PX, SOD and CAT activities and the reducing of MDA content compared with other samples. Furthermore, SPF samples, especially the SHD sample, could evidently ameliorate inflammation through the inhibition of IL-6, IL-1ß and TNF-α expression. All the studied SPF samples exhibited evidently inhibitory effects on the four enzymes. The IC50 values of inhibitory activity on α-glucosidase and α-amylase from SHD sample were 2.516 ± 0.024 and 0.734 ± 0.034 mg/mL, respectively. SD samples had potential inhibitory effects on cholinesterases and tyrosinase with IC50 values of 3.443 ± 0.060 and 1.732 ± 0.058 mg/mL. In consideration of active compound contents and biological activities, it was recommended that SHD and SD be applied for drying SPF at an industrial scale.

The Modulation of Electrokinetic Streaming Potentials of Silicon-Based Surfaces through Plasma-Based Surface Processing.

A new plasma processing-based methodology for enhancing the streaming potential (Vs) that may be obtained in electrokinetic flows for a given pressure gradient over a silicon surface-based microchannel is indicated. The dependence of the Vs on both the surface zeta potential and the electrolyte slip length was carefully determined through a series of experiments involving the variation of CF4- and Ar-based plasma parameters, incorporating pressure, exposure time, and power. It was determined through analytical estimates that, while the zeta potential is always increased, the slip length may be diminished under certain conditions. A record value of ∼0.1 mV/Pa was obtained using CF4 plasma at 500 W, 10 mTorr, and 300 s of exposure. The implications of the work extend to the investigation of whether smooth surfaces may be effective for generating large Vs's for new modalities of electrical voltage sources in microfluidics-based applications.

The association between sleep and empathy in young preschoolers: A population study.

Sleep is vital for children's early socio-emotional development, particularly empathy. This study aimed to explore the associations between sleep and empathy in young preschoolers. A sample of 23,259 preschoolers (4.3 ± 0.3 years) at the entry year of preschool was recruited as part of the Shanghai Children's Health, Education and Lifestyle Evaluation-Preschool (SCHEDULE-P) study. Caregivers reported on child sleep, affective empathy, and cognitive empathy through the Children's Sleep Habits Questionnaire and the Griffith Empathy Measure. Ordinary least-square regression and quantile regression were performed for the associations between sleep and empathy. Sex differences were also investigated. Night sleep duration was negatively associated with affective empathy (ß = -0.35, p < 0.001), and positively associated with cognitive empathy (ß = 0.41, p < 0.001). Longer nap duration was associated with higher affective empathy (ß = 0.28, p < 0.001). Sleep disturbances were positively associated with affective empathy (ß = 0.04, p < 0.001) and negatively associated with cognitive empathy (ß = -0.09, p < 0.001). These associations were generally stronger in children at higher empathy quantiles and also those at the 10th cognitive empathy quantile. The associations between sleep and affective empathy were mainly contributed by girls, and were more common in boys in terms of cognitive empathy, particularly at the 10th and the 30th quantiles. In conclusion, longer night sleep duration and fewer sleep disturbances are associated with a more mature empathy pattern in young preschoolers. The associations are more prominent in children at the higher end of the empathy spectrum, and vary by sex. These findings highlight the importance to promote sleep health in young children for optimal socio-emotional development.

Performance of common genetic variants in risk prediction for colorectal cancer in Chinese: A two-stage and multicenter study.

The efficacy of susceptible variants derived from genome-wide association studies (GWAs) optimizing discriminatory accuracy of colorectal cancer (CRC) in Chinese remains unclear. In the present validation study, we assessed 75 recently identified variants from GWAs. A risk predictive model combining 19 variants using the least absolute shrinkage and selection operator (LASSO) statistics offered certain clinical advantages. This model demonstrated an area under the receiver operating characteristic (AUC) of 0.61 during training analysis and yielded robust AUCs from 0.59 to 0.61 during validation analysis in three independent centers. The individuals carrying the highest quartile of risk score revealed over 2-fold risks of CRC (ranging from 2.12 to 2.90) compared with those who presented the lowest quartile of risk score. This genetic model offered the possibility of partitioning risk within the average risk population, which might serve as a first step toward developing individualized CRC prevention strategies in China.

Peroral targeting of drug micro or nanocarriers to sites beyond the gastrointestinal tract.

Targeted delivery of drug micro or nanocarriers has been attained via parenteral routes, especially the intravenous route. Conventionally, oral targeting refers to site-specific delivery and triggered drug release at local sites within the gastrointestinal tract (GIT), or targeting to the enteric epithelia through ligand-receptor or transporter interactions. Beyond that barrier, the concept of peroral targeting has not been clarified. Nevertheless, this is possible as long as drug carriers are able to be absorbed into the systemic circulation intact. Recent findings on in vivo translocation of drug micro or nanocarriers shed light on potential peroral targeting to remote sites beyond the GIT. Sequential processes of penetration across the enteric epithelia, transportation via the lymphatics and ultimate convergence with the systemic circulation are involved in the underlying mechanisms. The microfold cell (M cell) pathway plays a leading role in breaking through the enteric epithelial barrier. Accumulating evidence confirms primary targeting of a series of lipid and polymeric micro or nanocarriers to organs and tissues of the mononuclear phagocyte systems (MPS), such as the liver, spleen, lungs and kidneys. The total amount of lymph-bound particles could reach 8%, as evidenced by quantification of glucan microparticles that specifically bind M cell. Migration or translocation of micro or nanocarrier-bearing macrophages attains secondary targeting of the engulfed micro or nanocarriers to distant sites far beyond the MPS. The current findings foresee a probability of targeting to sites beyond the GIT. However, the content of exposure of micro or nanocarriers at target sites and potential therapeutic or diagnostic promises are yet to be unraveled.

Adaptive beam shaping for enhanced underwater wireless optical communication.

In this paper, we proposed and experimentally verified a diffraction-based optical beam shaping technique for underwater optical communication (UWOC) applications. The proposed method aimed to address the key issue in UWOC links, i.e., the high propagation loss experienced by the launched optical beam. It enabled a significantly higher portion of the launched signal to be collected by the receiver. The optimal transmission distance could also be fine-tuned by the software configuration. In a proof-of-concept demonstration based on the off-the-shelf components, 100 Mbps transmission was achieved over 15-meter distance and a significant enhancement in the transmission quality was observed. There is a huge scope for further improvement in the transmission distance and data rate when the proposed technique was used with purpose-built optical components and advanced coding schemes.

Influence of Surface Texture on the Variation of Electrokinetic Streaming Potentials.

The electrokinetic streaming potential (Vs) obtained through electrolyte flow in a microchannel is shown to be related to the underlying surface pattern. Pillar, mesh, and groove patterns were studied for comparing the relative magnitudes of the Vs with air-/liquid-filled surfaces. A record value of the related figure of merit, in terms of the developed Vs per-unit applied pressure, of ∼0.127 mV/Pa, was observed in a mesh texture liquid-filled surface (LFS) impregnated with an electrolyte-immiscible oil. The study indicated that increasing the solid fraction of the pattern surface decreases the effective slip length while enhancing the overall channel ζ potential. Consequently, maximizing the obtained Vs implies a balancing of the slip with the surface potential, with plausibly more significance of the latter. The work has implications for higher-efficiency electrical voltage sources.

Construction of Aptamer-Based Molecular Beacons with Varied Blocked Structures and Targeted Detection of Thrombin.

A kind of blocked aptamer-functionalized molecular beacon (MB) was designed as fluorescence sensors to detect thrombins by binding-induced "turn on" structural transformation. Three MBs named MB(8 + 8), MB(15 + 8), and MB(15 + 6) consisted of two single-stranded oligonucleotides. One long single-stranded oligonucleotide (abbreviated as SS) contained a thrombin aptamer sequence and was modified with a fluorescence group and quenching group on each end side. Another short single-stranded oligonucleotide (written as cDNA) was partially complementary to the long SS. It was interesting to find that the complementary sequence length of cDNA greatly influenced the structure of the MBs. The construction of MB experiments proved that MB(8 + 8) and MB(15 + 8) could form the quenching MBs but MB(15 + 6) could not. MB(8 + 8) was composed of a SS strand paired with a complementary cDNA(8 + 8), which was called one-to-one combination, while MB(15 + 8) was two-to-two combination and MB(15 + 6) was one-to-two combination. When the ratio of SS and cDNA (15 + 8) was 1:1, the quenching efficiency reached maximum. But with the molar ratio of SS and cDNA(8 + 8) increasing, the quenching efficiency increased continuously. Under the optimal conditions that we studied, the detection limit of thrombin by MB(8 + 8) and MB(15 + 8) was 0.19 and 1.2 nM, respectively. In addition, the assay proved to be selective, and the average recovery of thrombin detected by MB(8 + 8) and MB(15 + 8) in diluted serum was 95.4 and 94.5%, respectively.