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This paper proposes a numerical modeling method to construct finite element models of randomly pitted steel Circular Hollow Section (CHS) T-joints. A series of parametric analyses were conducted on joints under axial brace compression to study the effect of geometric properties, such as the brace-to-chord diameter ratio, β , and chord diameter-to-thickness ratio, 2 γ , on the ultimate strength under varying degrees of volume loss of corroded material (DOV). The synergy of key geometric properties and corrosion damage was clarified. The results indicated that the joints with a smaller β or a larger 2 γ exhibited a larger reduction in ultimate strength under the same DOV. Moreover, due to the stress concentration stemming from irregular corrosion pits, the ultimate strength of a randomly pitted joint was nearly 10% lower than that with general corrosion. In particular, a significant variation in the ultimate strength of a randomly pitted joint was observed under a certain DOV, following a normal distribution. A correction factor was proposed to account for the impact of pitting corrosion on ultimate strength. This factor was then utilized to modify the CIDECT mean strength equation, leading to high accuracy in predicting the ultimate strength, with mean relative errors of less than 5%. • Propose a novel modeling method to mimic random pitting corrosion on CHS T-joints. • Identify key geometric properties affecting the ultimate strength of randomly pitted joints. • Clarify the synergy of pitting corrosion and geometric properties on strength reduction. • Define a correction coefficient to account for the pitting damage effect on ultimate strength. [ABSTRACT FROM AUTHOR]

Eukaryotic elongation factor 2 (eEF2) mediates translocation of peptidyl-tRNA from the ribosomal A site to the P site to promote translational elongation. Its phosphorylation on Thr56 by its single known kinase eEF2K inactivates it and inhibits translational elongation. Extensive studies have revealed that different signal cascades modulate eEF2K activity, but whether additional factors regulate phosphorylation of eEF2 remains unclear. Here, we find that the X chromosome-linked intellectual disability protein polyglutamine-binding protein 1 (PQBP1) specifically binds to non-phosphorylated eEF2 and suppresses eEF2K-mediated phosphorylation at Thr56. Loss of PQBP1 significantly reduces general protein synthesis by suppressing translational elongation. Moreover, we show that PQBP1 regulates hippocampal metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD) and mGluR-LTD-associated behaviors by suppressing eEF2K-mediated phosphorylation. Our results identify PQBP1 as a novel regulator in translational elongation and mGluR-LTD, and this newly revealed regulator in the eEF2K/eEF2 pathway is also an excellent therapeutic target for various disease conditions, such as neural diseases, virus infection, and cancer. [Display omitted] • Cytoplasmic PQBP1 binds to non-phosphorylated eEF2 at a linear peptide around Thr56 • PQBP1 suppresses eEF2K-mediated phosphorylation at Thr56 • Loss of PQBP1 reduces protein synthesis by suppressing translational elongation • PQBP1 regulates hippocampal mGluR-LTD by suppressing eEF2K-mediated phosphorylation Translation elongation controls the efficiency and accuracy of protein synthesis. Shen et al. discover that the intellectual disability-associated protein PQBP1 regulates translation elongation by direct interaction with eEF2, protecting it from phosphorylation. Loss of PQBP1 in hippocampal neurons impairs metabotropic glutamate receptor-induced long-term depression and associated behaviors. [ABSTRACT FROM AUTHOR]

We aimed to determine the prognosis value of circulating tumor cells (CTCs) undergoing epithelial–mesenchymal transition in epithelial ovarian cancer (EOC) recurrence. We used CanPatrol CTC-enrichment technique to detect CTCs from blood samples and classify subpopulations into epithelial, mesenchymal, and hybrids. To construct nomogram, prognostic factors were selected by Cox regression analysis. Risk stratification was performed through Kaplan–Meier analysis among the training group (n = 114) and validation group (n = 38). By regression screening, both CTC counts (HR 1.187; 95% CI 1.098–1.752; p = 0.012) and M-CTC (HR 1.098; 95% CI 1.047–1.320; p = 0.009) were demonstrated as independent factors for recurrence. Other variables including pathological grade, FIGO stage, lymph node metastasis, ascites, and CA-125 were also selected (p < 0.005) to construct nomogram. The C-index of internal and external validation for nomogram was 0.913 and 0.874. We found significant predictive values for the nomogram with/without CTCs (AUC 0.8705 and 0.8097). Taking CTC counts and M-CTC into separation, the values were 0.8075 and 0.8262. Finally, survival curves of risk stratification based on CTC counts (p = 0.0241), M-CTC (p = 0.0107), and the nomogram (p = 0.0021) were drawn with significant differences. In conclusion, CTCs could serve as a novel factor for EOC prognosis. Nomogram model constructed by CTCs and other clinical parameters could predict EOC recurrence and perform risk stratification for clinical decision-making. Trial registration Chinese Clinical Trial Registry, ChiCTR-DDD-16009601, October 25, 2016. [ABSTRACT FROM AUTHOR]

• The mineralization at the Longgen deposit occurred in the Paleocene. • Syn-collisional magmatism shows great potential for the formation of Pb-Zn/Fe-Cu mineralization. • Different magmatic sources are beneficial for different mineralization events. • Slab rollback and subsequent breakoff controlled the major mineralization events. Syn-collisional orogeny generally lacks adequate fluids and has a low potential to form magmatic hydrothermal ore deposits. However, some syn-collisional Pb–Zn deposits have been recognized in the Nyainqentanglha polymetallic belt (NPB), central Lhasa subterrane and ore-related magma petrogenesis and the metallogenic geodynamic setting is limited. In this study, detailed petrology, geochemical and geochronological data of ore-related syn-collisional granite porphyries are evaluated to constrain the timing of mineralization and discuss the genesis and evolution of ore-related magma using the Longgen skarn Pb–Zn deposit as a case study. Zircon U–Pb dating of ore-related porphyries provides a weighted mean age of 61.2 ± 0.8 Ma, which is slightly earlier than the sphalerite Rb–Sr age of 59.1 ± 3.0 Ma, indicating that a Paleocene Pb–Zn mineralization event occurred during syn-collisional orogeny. The porphyries have high SiO 2 , K 2 O + Na 2 O, and are enriched in Rb, Th, U, Pb, LREEs, and A/CNK (0.94–1.15), but have low P 2 O 5 and are depleted in Nb, Ta, and Ti. This suggests that the Longgen granite porphyries are metaluminous to weakly peraluminous high-K calc-alkaline "arc-like" granites. These porphyries have highly radiogenic isotopic compositions with (87Sr/86Sr) i 0.709513–0.713587, (207Pb/204Pb) i 15.657–15.713, and (208Pb/204Pb) i 38.964–39.163, but low ε Nd (t) values from − 6.7 to − 6.0, as well as negative zircon ε Hf (t) values from − 5.1 to − 3.2, corresponding to T DM 2(Nd) ages of 1.37 to 1.42 Ga and zircon Hf T DM c ages of 1.30 to 1.42 Ga. This demonstrates that the Longgen granite porphyries may have been generated by the partial melting of Mesoproterozoic basement continental crust materials with significant amounts (30–50%) of mantle-derived melt input. Paleocene-Eocene (65–45 Ma) magmatic rocks associated with Pb–Zn and Fe–Cu deposits are compiled in the NPB. The Pb–Zn ore-related granitoids have relatively lower whole-rock ε Nd (t) and zircon ε Hf (t) values, higher (87Sr/86Sr) i values, and older T DM C ages than the coeval granitoids associated with Fe–Cu mineralization. This indicates that mantle material is more critical for the development of Fe–Cu ore-related granitoids than granitoids associated with Pb–Zn mineralization. The final results show that different sources of Paleocene–Eocene syn-collisional magma in the NPB are beneficial for different mineralization events during the syn-collisional orogeny of the Indian and Asian plates. [ABSTRACT FROM AUTHOR]

• Effect of foundry sand waste (FDW) on SCC mixed with RHA was studied. • RHA was replaced in Portland Cement Type 1 by 10 and 20%wt. • FDW was used as a fine aggregate replacement by 30 and 50%wt. • Incorporation of RHA and FDW decreased the filling and passing ability of SCC. • At 10%wt RHA-SCC with 30%wt foundry sand waste achieved the highest strength. The combined advantages of wastes in high-performance concrete production are currently popular topics of investigation. This study aims to examine the effect of foundry sand waste (FDW) as a fine aggregate replacement (30 and 50%wt) on the properties of self-consolidating concrete (SCC) mixed with untreated rice husk ash (RHA) as a cement replacement (10 and 20%wt) with controlling water-binder materials ratios (w/b) of 0.35 and 0.45. The workability and strength characteristics of SCC are considered. The results indicate that the increase in FDW amount affects the SCC with RHA, increases the required superplasticizer and setting times compared to the control SCC, and decreases the density and slump flow loss. The incorporation of RHA and FDW decreases the filling and passing ability of the SCC. Based on the workability requirements specified by EFNARC guidelines, SCC mixtures exhibited acceptable V-funnel performance at replacement levels of RHA and FDW not more than 10 and 30 wt% and achieved the highest compressive and splitting strengths. [ABSTRACT FROM AUTHOR]

Background: Increasing researches have demonstrated the critical functions of circular RNAs (circRNAs) in the progression of malignant tumors, including ovarian cancer. In this study, we aim to investigate abnormally expression of hsa_circ_0078607 and the role of hsa_circ_0078607 during ovarian cancer pathogenesis. Methods: RT-PCR were used to detect the expression of circ_0078607 in ovarian cancer tissues. To determine the functional roles of circ_0078607 in ovarian cancer, cell proliferation and cell invasion assays were performed. Bioinformatics and luciferase reporter analysis were used to predict the target of circ_0078607. Results: In the present study, we first found that circ_0078607 was downregulated in ovarian cancer. Forced circ_0078607 expression significantly suppressed proliferation and promoted apoptosis of ovarian cancer cells. Mechanically, bioinformatics and luciferase reporter analysis identified miR-518a-5p as a direct target of circ_0078607, while Fas as a direct target of miR-518a-5p. MiR-518a-5p negatively regulated Fas in ovarian cancer cells, while overexpression of circ_0078607 could increase the expression of Fas inhibited by miR-518a-5p. Furthermore, overexpression of circ_0078607 could inhibit the proliferation and invasion of ovarian cancer cells caused by miR-518a-5p mimic. Conclusion: The results of the present study revealed that circ_0078607 suppressed ovarian cancer progression by sponging oncogenic miR-518a-5p to induce Fas expression, which may provide new therapeutic approach for ovarian cancer. [ABSTRACT FROM AUTHOR]

Highlights • Investigate the compressive behavior of the RAC under cyclic loading. • Analyze the effects of the RCA replacement percentage on the behavior of the RAC. • Propose the constitutive equations of the RAC under cyclic loading. • Develop the UMAT subroutine of the proposed constitutive equations in ABAQUS. Abstract This paper has focused on the structural performance of recycled aggregate concrete (RAC) under both cyclic and monotonic loading. RAC specimens with different recycled coarse aggregate (RCA) replacement percentages of 0%, 25%, 50%, 75% and 100% were cast and tested. The compressive stress-strain relationship and the failure mode were investigated for each RCA replacement ratio. The effects of the RCA replacement percentage on the compressive mechanical properties of the RAC specimens including the strength, elastic modulus, peak strain, ultimate strain and Poisson's ratio were also studied. The RAC specimens have shown similar failure characteristics regardless of monotonic or cyclic loading. In addition, the compression skeleton curves of the RAC specimens under cyclic loading agree well with those under monotonic loading. Based on the experimental results, the characteristic points pertaining to the hysteresis loop were defined and their relations were established. Furthermore, the constitutive equations of the RAC as well as its simplified form were proposed and applied in numerical simulations of RAC columns and frames under cyclic loading. The proposed constitutive equations have shown promising accuracy in predicting the hysteresis performance of RAC on both component and structural levels. [ABSTRACT FROM AUTHOR]

The uniaxial compressive tests were carried out to investigate the post-fire compressive stress–strain behaviour of steel fibre reinforced recycled aggregate concrete (SFR-RAC) after being exposed to elevated temperatures. The test parameters include water-to-cement ratio, recycled concrete aggregate (RCA) substituting ratio, steel fibre content and heated temperature. The failure mode, strength, elastic modulus, peak strain, and strain–stress response of the tested specimens are analysed. The test results show that the compressive strength and elastic modulus decreased with the increase of water-to-cement ratio and/or RCA substituting ratio at any exposed temperature. The residual strength retained about 83%, 85%, 56% and 23% of their ambient compressive strength on average after being exposed to 200, 400, 600 and 800 °C, respectively. The steel fibre has a positive effect on the residual mechanical properties and its effect increases with the increase of heated temperature. Based on the test data, a simplified explicit formula was proposed for predicting the compressive strength, peak strain, elastic modulus, and uniaxial compressive stress–strain constitutive model of the SFR-RAC. [ABSTRACT FROM AUTHOR]

Twenty-four full-scale tests were carried out in order to investigate the post-fire behaviour of UHPCFST stub columns under axial compression after being exposed to elevated temperatures. The test parameters include cross-sectional size, heating mode, steel fibre content, and coarse aggregate content. The failure modes, cross-sectional historical maximum temperatures, axial load-deformation curves, and residual compressive capacities of the specimens are analysed. The test results revealed non-uniform and nonlinear distributions of the cross-sectional historical-max temperatures. It is found that the effect of historical temperature on the residual capacity of a UHPCFST column is more obvious with the increase of the heating rate and decrease of the cross-sectional size. Inspired by the concept of average temperature method under fire, a method for calculating the post-fire residual load capacity of CFST columns was proposed based on the average historical-max temperature of the cross-section. High accuracy has been found for using the proposed calculation method, therefore the work could serve as a reference for the post-fire assessment and strengthening of UHPCFST stub columns. • Full-scale UHPCFST stub columns were tested after elevated temperatures under axial compression. • The effect of UHPC mixture, sectional size and heating mode on post-fire behaviour of UHPCFST stub columns were analysed. • A method for calculating the residual capacity of CFST columns based on average historical-max temperature was proposed. [ABSTRACT FROM AUTHOR]

In this paper, a semi-analytical model is proposed to solve the diffraction problem from a cylinder with a moonpool. The cylinder and the moonpool can be in arbitrary shapes. Linear potential flow theory and eigenfunction matching method are adopted in the analytical model. After dividing the fluid domain into three regions (i.e., the region beneath the cylinder; the inner region enclosed by the cylinder; the exterior region outer the cylinder), diffracted spatial potentials in each region can be expressed by a series of eigenfunctions. The continuity conditions between adjacent regions together with a Fourier series method combined with the eigenfunction matching method are employed to determine the unknown coefficients in the expressions of diffracted potentials. The well-known potential of incident waves and the obtained diffracted potentials are then used to directly compute the wave excitation forces/moments acting on the cylinder and the wave excitation volume flux. Analytical results of wave excitation forces/moments and volume flux are compared with the numerical results obtained by using a boundary element method numerical solver. Wave diffraction from the cases with different shapes of either cylinder hull or moonpool is finally tested with the semi-analytical model. • A semi-analytical model is proposed to solve wave diffraction from a cylinder with a moonpool. • The cylinder and the moonpool can be in arbitrary shapes. • Good agreement is found between the present model and WAMIT. • Wave diffraction from the cases with different shapes of either cylinder hull or moonpool is tested. [ABSTRACT FROM AUTHOR]

Stability of the platform is the most fundamental guarantee for floating offshore wind turbines. In order to explore hydrodynamics of floating wind turbine Spar platform under the coupling effect of wind and wave, whole model of floating wind turbine is established based on the OC3-Hywind Spar Buoy platform and the NREL 5 MW wind turbine. Taking the research experiences of traditional marine engineering, this work proposed the structural design method of installing heave plate on main body of Spar. Based on the Bladed Element Momentum theory, this paper adopts FORTRAN language to accomplish the secondary development of hydrodynamic software AQWA to establish the coupled aerodynamic - hydrodynamic - mooring line system model. The amplitude-frequency curves of the added mass, radiation damping, wave exciting force and response amplitude operators (RAO) were obtained based on radiation/diffraction theory to investigate the hydrodynamic performance of floating wind turbine Spar platform in frequency domain. In the time-domain analysis, the three kinds of working conditions include wave-only, non-coupling effect of wind-wave and coupling effect of wind-wave were conducted comparatively to verify the importance of wind load and wind - wave interaction. In addition, the actual motions of original Spar and Spar with heave plates were analyzed to explore the effects of the heave plate and its installation position on the nonlinear dynamic response characteristics of Spar under the coupling effect of wind and wave. The research results indicated that the installation position of the heave plate has little influence on the surge response. In view of the actual heave motion, the heave plate can play a positive effect no matter where the heave plate is installed. When the heave plate is located on the upper part of the platform, the pitch response and the intensity of the fluctuation of the platform will be greatly reduced. Finally, time domain mooring analysis for Spar platform with and without heave plate is performed to illustrate the feasibility of the present approach for mooring modeling. • A coupled aerodynamic - hydrodynamic - mooring line system model was established based on a secondary development of AQWA. • The coupling effect of wind and wave was considered and its importance was verified. • The effects of heave plate and its installation position on the dynamic response of floating wind turbine were investigated. [ABSTRACT FROM AUTHOR]

Lead-halide perovskite nanocrystals (NCs) have gained significant attention for their promising applications in lighting and display technologies. However, blue-emitting NCs have struggled to match the high efficiency of their red and green counterparts. Moreover, many reported blue-emitting perovskite NCs contain heavy metal lead (Pb), which poses risks to human health and the environment. In this study, we synthesized rare-earth-based Cs 3 TmCl 6 NCs via the hot injection method, which exhibit a broadband blue emission at 440 nm. Combined experimental and theoretical studies indicate that the broadband emission in Cs 3 TmCl 6 arises from self-trapped excitons due to the excited-state structural distortion of the [TmCl 6 ] 3- cluster. Furthermore, the ultrafast dynamics of charge carriers were analyzed using time-resolved photoluminescence and transient absorption measurements. Encouraged by the remarkable thermal, light, and water stabilities of Cs 3 TmCl 6 NCs, as evidenced by experimental and theoretical results, a white light-emitting diode was further designed and fabricated using the Cs 3 TmCl 6 NCs as the color converter. The device exhibits outstanding performance, achieving a long half-lifetime of 336 h and a large color-rendering index of 87.0. Combining eco-friendly features and a facile synthesis method, the rare-earth-based Cs 3 TmCl 6 NCs mark a significant breakthrough as a reliable blue emitter, showcasing their future potential in lighting and display applications.

Although many susceptibility loci for IgA nephropathy (IgAN) have been identified, they only account for 11.0% of the overall IgAN variance. We performed a large genome-wide meta-analysis of IgAN in Han Chinese with 3616 cases and 10 417 controls to identify additional genetic loci of IgAN. Considering that inflammatory bowel disease (IBD) and asthma might share an etiology of dysregulated mucosal immunity with IgAN, we performed cross-trait integrative analysis by leveraging functional annotations of relevant cell type and the pleiotropic information from IBD and asthma. Among 8 669 456 imputed variants, we identified a novel locus at 4p14 containing the long noncoding RNA LOC101060498. Cell type enrichment analysis based on annotations suggested that PMA-I-stimulated CD4 + CD25 - IL17 + Th17 cell was the most relevant cell type for IgAN, which highlights the essential role of Th17 pathway in the pathogenesis of IgAN. Furthermore, we identified six more novel loci associated with IgAN, which included three loci showing pleiotropic effects with IBD or asthma (2q35/PNKD, 6q25.2/SCAF8, and 22q11.21/UBE2L3) and three loci specific to IgAN (14q32.32/TRAF3, 16q22.2/TXNL4B, and 21q21.3/LINC00113) in the pleiotropic analysis. Our findings support the involvement of mucosal immunity, especially T cell immune response and IL-17 signal pathway, in the development of IgAN and shed light on further investigation of IgAN., (© 2024. Higher Education Press.)

Epigenome-wide association studies (EWAS) are susceptible to widespread confounding caused by population structure and genetic relatedness. Nevertheless, kinship estimation is challenging in EWAS without genotyping data. Here, we proposed MethylGenotyper, a method that for the first time enables accurate genotyping at thousands of single nucleotide polymorphisms (SNPs) directly from commercial DNA methylation microarrays. We modeled the intensities of methylation probes near SNPs with a mixture of three beta distributions corresponding to different genotypes and estimated parameters with an expectation-maximization algorithm. We conducted extensive simulations to demonstrate the performance of the method. When applying MethylGenotyper to the Infinium EPIC array data of 4662 Chinese samples, we obtained genotypes at 4319 SNPs with a concordance rate of 98.26%, enabling the identification of 255 pairs of close relatedness. Furthermore, we showed that MethylGenotyper allows for the estimation of both population structure and cryptic relatedness among 702 Australians of diverse ancestry. We also implemented MethylGenotyper in a publicly available R package (https://github.com/Yi-Jiang/MethylGenotyper) to facilitate future large-scale EWAS., (© The Author(s) 2024. Published by Oxford University Press and Science Press on behalf of the Beijing Institute of Genomics, Chinese Academy of Sciences / China National Center for Bioinformation and Genetics Society of China.)

Organic thin film transistors (OTFTs) enable rapid and label-free high-sensitivity detection of target analytes due to their low cost, large-area processing, biocompatibility, and inherent signal amplification. At the same time, the freedom of synthesis, tailorability, and functionalization of organic semiconductor materials and their ability to be combined with flexible substrates make them one of the ideal platforms for biosensing. However, OTFTs-based biosensors still face significant challenges, such as unexpected surface adsorption, disordered conformation, inhomogeneous graft density, and flexibility of probe molecules that biological sensing probes would face during immobilization. In this review, efficient immobilization strategies based on OTFTs biological sensing probes developed in the last 5 years are highlighted. First, the biosensors are classified according to their sensing interface. Second, a comprehensive discussion of the types of biological sensing probes is presented. Third, three commonly used methods for immobilizing biological sensing probes and their challenges are briefly described. Finally, the applications of OTFTs-based biosensors for liquid phase detection are summarized. This review provides a comprehensive and timely review of optimization in sensing interface engineering so that efficient immobilization of biological sensing probes with sensing interfaces will contribute to the development of high-performance OTFTs-based biosensors., (© 2024 Wiley‐VCH GmbH.)

Neurite outgrowth is a critical step in neural development, leading to the generation of neurite branches that allow individual neurons to make contacts with multiple neurons within the target region. Polyglutamine-binding protein 1 (PQBP1) is a highly conserved protein with a key role in neural development. Our recent mass spectrometric analysis showed that PQBP1 associates with neural Wiskott-Aldrich syndrome protein (N-WASP), an important actin polymerization-promoting factor involved in neurite outgrowth. Here, we report that the WW domain of PQBP1 directly interacts with the proline-rich domain of N-WASP. The disruption of this interaction leads to impaired neurite outgrowth and growth cone size. Furthermore, we demonstrate that PQBP1/N-WASP interaction is critical for the recruitment of N-WASP to the growth cone, but does not affect N-WASP protein levels or N-WASP-induced actin polymerization. Our results indicated that PQBP1 regulates neurite outgrowth by recruiting N-WASP to the growth cone, thus representing an alternative molecular mechanism via which PQBP1-mediates neurite outgrowth., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Pancreatic cancer (PC) is the deadliest malignancy due to late diagnosis. Aberrant alterations in the blood proteome might serve as biomarkers to facilitate early detection of PC. We designed a nested case-control study of incident PC based on a prospective cohort of 38,295 elderly Chinese participants with ∼5.7 years' follow-up. Forty matched case-control pairs passed the quality controls for the proximity extension assay of 1,463 serum proteins. With a lenient threshold of p < 0.005, we discovered regenerating family member 1A (REG1A), REG1B, tumor necrosis factor (TNF), and phospholipase A2 group IB (PLA2G1B) in association with incident PC, among which the two REG1 proteins were replicated using the UK Biobank Pharma Proteomics Project, with effect sizes increasing steadily as diagnosis time approaches the baseline. Mendelian randomization analysis further supported the potential causal effects of REG1 proteins on PC. Taken together, circulating REG1A and REG1B are promising biomarkers and potential therapeutic targets for the early detection and prevention of PC., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Mitochondrial DNA copy number (mtDNA-CN) is associated with the severity and mortality in patients with stroke, but the associations in different stroke subtypes remain unexplored., Methods: We conducted an observational prospective cohort analysis on patients with ischemic stroke or transient ischemic attack enrolled in the Third China National Stroke Registry. We applied logistic models to assess the association of mtDNA-CN with functional outcome (modified Rankin Scale score, 3-6 versus 0-2) and Cox proportional hazard models to assess the association with stroke recurrence (treating mortality as a competing risk) and mortality during a 12-month follow-up, adjusting for sex, age, physical activity, National Institutes of Health Stroke Scale at admission, history of stroke and peripheral artery disease, small artery occlusion, and interleukin-6. Subgroup analyses stratified by age and stroke subtypes were conducted., Results: The Third China National Stroke Registry enrolled 15 166 patients, of which 10 241 with whole-genome sequencing data were retained (mean age, 62.2 [SD, 11.2] years; 68.8% men). The associations between mtDNA-CN and poststroke/transient ischemic attack outcomes were specific to patients aged ≤65 years, with lower mtDNA-CN significantly associated with stroke recurrence in 12 months (subdistribution hazard ratio, 1.15 per SD lower mtDNA-CN [95% CI, 1.04-1.27]; P =5.2×10 -3 ) and higher all-cause mortality in 3 months (hazard ratio, 2.19 [95% CI, 1.41-3.39]; P =5.0×10 -4 ). Across subtypes, the associations of mtDNA-CN with stroke recurrence were specific to stroke of undetermined cause (subdistribution hazard ratio, 1.28 [95% CI, 1.11-1.48]; P =6.6×10 -4 ). In particular, lower mtDNA-CN was associated with poorer functional outcomes in stroke of undetermined cause patients diagnosed with embolic stroke of undetermined source (odds ratio, 1.53 [95% CI, 1.20-1.94]; P =5.4×10 -4 ), which remained significant after excluding patients with recurrent stroke (odds ratio, 1.49 [95% CI, 1.14-1.94]; P =3.0×10 -3 )., Conclusions: Lower mtDNA-CN is associated with higher stroke recurrence rate and all-cause mortality, as well as poorer functional outcome at follow-up, among stroke of undetermined cause, embolic stroke of undetermined source, and younger patients., Competing Interests: Disclosures None.

Ovarian cancer (OC) is one of the most common reproductive tumors in women, whereas current treatment options are limited. β-lactamase-like-protein 2 (LACTB2) has been observed to be associated with various cancers, but its function in OC is unknown. Therefore, we evaluate the prognostic value and the underlying function of LACTB2 in OC. In this study, high expression of LACTB2 was observed in OC compared with normal controls. Kaplan-Meier Plotter analysis revealed that overexpressed LACTB2 is strongly correlated with poor prognosis. We conducted GO/KEGG analysis to investigate the potential biological function of LACTB2 in OC. GESA analysis showed that LACTB2 was closely related to immune-related pathways. Subsequently, we explored the relationship between LACTB2 and 24 types of immune cells in OC. The results suggested that LACTB2 was positively associated with multiple tumor-infiltrating immune cells. Importantly, LACTB2 may modulate immune cell infiltration in OC to influence prognosis. In conclusion, LACTB2 can be used as a promising prognostic biomarker and immunotherapy target for OC., (© 2024. The Author(s).)

Background: Disorders associated with cognitive impairment impose a significant burden on both families and society. Previous studies have indicated that gait characteristics under dual-task as reliable markers of early cognitive impairment. Therefore, digital gait detection has great potential for future cognitive screening. However, research on digital biomarkers based on smart devices to identify cognitive impairment remains limited. The aim of this study is to explore digital gait biomarkers by utilizing intelligent wearable devices for discriminating mild cognitive impairment and dementia., Methods: This study included 122 subjects (age: 74.7 ± 7.7 years) diagnosed with normal cognition (NC, n  = 38), mild cognitive impairment (MCI, n  = 42), or dementia ( n  = 42). All subjects underwent comprehensive neuropsychological assessments and cranial Magnetic Resonance Imaging (MRI). Gait parameters were collected using validated wearable devices in both single-task and dual-task (DT). We analyzed the ability of gait variables to predict MCI and dementia, and examined the correlations between specific DT-gait parameters and sub-cognitive functions as well as hippocampal atrophy., Results: Our results demonstrated that dual-task could significantly improve the ability to predict cognitive impairment based on gait parameters such as gait speed (GS) and stride length (SL). Additionally, we discovered that turn velocity (TV and DT-TV) can be a valuable novel digital marker for predicting MCI and dementia, for identifying MCI (DT-TV: AUC = 0.801, sensitivity 0.738, specificity 0.842), and dementia (DT-TV: AUC = 0.923, sensitivity 0.857, specificity 0.842). The correlation analysis and linear regression analysis revealed a robust association between DT-TV and memory function, as well as the hippocampus atrophy., Conclusion: This study presents a novel finding that DT-TV could accurately identify varying degrees of cognitive impairment. DT-TV is strongly correlated with memory function and hippocampus shrinkage, suggests that it can accurately reflect changes in cognitive function. Therefore, DT-TV could serve as a novel and effective digital biomarker for discriminating cognitive impairment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wang, Zhou, Cheng, Zhou, Sun, Song, Wu, Lu, Qin and Wang.)

Fluorescence thermometry has been propelled to the forefront of scientific attention due to its high spatial resolution and remote non-invasive detection. However, recent generations of thermometers still suffer from limited thermal sensitivity (S r ) below 10% change per Kelvin. Herein, this work presents an ideal temperature-responsive fluorescence material through Te 4+ -doped 0D Cs 2 ScCl 5 ·H 2 O, in which isolated polyhedrons endow highly localized electronic structures, and the strong electron-phonon coupling facilitates the formation of self-trapped excitons (STEs). With rising temperature, the dramatic asymmetric expansion of the soft lattice induces increased defects, strong exciton-phonon coupling, and low thermal activation energy, which evokes a rapid de-trapping process of STEs, enabling several orders of magnitude changes in the fluorescence lifetime over a narrow temperature range. After regulating the de-trapping process with different Te 4+ doping, a record-high S r (27.36% K -1 ) of fluorescence lifetime-based detection is achieved at 325 K. The robust stability against multiple heating/cooling cycles and long-term measurements enables a low temperature uncertainty of 0.067 K. Further, the developed thermometers are demonstrated for the remote local monitoring of operating temperature on internal electronic components. It is believed that this work constitutes a solid step towards building the next generation of ultrasensitive thermometers based on low-dimensional metal halides., (© 2023 Wiley-VCH GmbH.)

Organic field effect transistors have emerged as promising platforms for biosensing applications. However, the challenge lies in optimizing functionalization strategies for the sensing interface, enabling the simultaneous detection of low abundance proteins while maintaining device performance. Here, we designed a carbon dots-functionalized extended gate organic field effect transistor. Leveraging the advantages of facile synthesis, tunable modification, small particle size, and cost-effectiveness of carbon dots, we implemented their integration onto the electrode surface. Through harnessing the covalent interactions of functional groups on the surface of carbon dots, we achieved effective immobilization of low abundance proteins without compromising device performance. Consequently, this biosensor exhibits a remarkably low limit of detection of 2.7 pg mL -1 and demonstrates high selectivity for the carcinoembryonic antigen. These findings highlight the superior capabilities of carbon dots in enhancing biosensor performance and emphasize their potential for early cancer detection.

Enhancers, which are key tumorigenic factors with wide applications for subtyping, diagnosis and treatment of cancer, are attracting increasing attention in the cancer research. However, systematic analysis of cancer enhancers poses a challenge due to the lack of integrative data resources, especially those from tumor primary tissues. To provide a comprehensive enhancer profile across cancer types, we developed a cancer enhancer database CenhANCER by curating public resources including all the public H3K27ac ChIP-Seq data from 805 primary tissue samples and 671 cell line samples across 41 cancer types. In total, 57 029 408 typical enhancers, 978 411 super-enhancers and 226 726 enriched transcription factors were identified. We annotated the super-enhancers with chromatin accessibility regions, cancer expression quantitative trait loci (eQTLs), genotype-tissue expression eQTLs and genome-wide association study risk single nucleotide polymorphisms (SNPs) for further functional analysis. The identified enhancers were highly consistent with accessible chromatin regions in the corresponding cancer types, and all the 10 super-enhancer regions identified from one colorectal cancer study were recapitulated in our CenhANCER, both of which testified the high quality of our data. CenhANCER with high-quality cancer enhancer candidates and transcription factors that are potential therapeutic targets across multiple cancer types provides a credible resource for single cancer analysis and for comparative studies of various cancer types. Database URL http://cenhancer.chenzxlab.cn/., (© The Author(s) 2023. Published by Oxford University Press.)

Mutations in the polyglutamine tract-binding protein 1 (PQBP1) gene are associated with Renpenning syndrome, which is characterized by microcephaly, intellectual deficiency, short stature, small testes, and distinct facial dysmorphism. Studies using different models have revealed that PQBP1 plays essential roles in neural development and function. In this mini-review, we summarize recent findings relating to the roles of PQBP1 in these processes, including in the regulation of neural progenitor proliferation, neural projection, synaptic growth, neuronal survival, and cognitive function via mRNA transcription and splicing-dependent or -independent processes. The novel findings provide insights into the mechanisms underlying the pathogenesis of Renpenning syndrome and may advance drug discovery and treatment for this condition., (© 2023 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Ovarian cancer (OV) is the most lethal form of gynecological malignancy worldwide, with limited therapeutic options and high recurrence rates. However, research focusing on prognostic patterns of ferroptosis-related genes (FRGs) in ovarian cancer is still lacking. From the 6,406 differentially expressed genes (DEGs) between TCGA-OV ( n = 376) and GTEx cohort ( n = 180), we identified 63 potential ferroptosis-related genes. Through the LASSO-penalized Cox analysis, 3 prognostic genes, SLC7A11, ZFP36, and TTBK2, were finally distinguished. The time-dependent ROC curves and K-M survival analysis performed powerful prognostic ability of the 3-gene signature. Stepwise, we constructed and validated the nomogram based on the 3-gene signature and clinical features, with promising prognostic value in both TCGA ( p -value < .0001) and ICGC cohort ( p -value = .0064). Gene Set Enrichment Analysis elucidated several potential pathways between the groups stratified by 3-gene signature, while the m6A gene analysis implied higher m6A level in the high-risk group. We applied the CIBERSORT algorithm to distinct tumor immune microenvironment between two groups, with less activated dendritic cells (DCs) and plasma cells, more M0 macrophages infiltration, and higher expression of key immune checkpoint molecules (CD274, CTLA4, HAVCR2, and PDCD1LG2) in the high-risk group. In addition, the low-risk group exhibited more favorable immunotherapy and chemotherapy responses. Collectively, our findings provided new prospects in the role of ferroptosis-related genes, as a promising prediction tool for prognosis and immune responses, in order to assist personalized treatment decision-making among ovarian cancer patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Yang, Wang, Cheng, Zhang, Jin, Zhang and Wang.)

Background: Tumor pathology can assess patient prognosis based on a morphological deviation of tumor tissue from normal. Digitizing whole slide images (WSIs) of tissue enables the use of deep learning (DL) techniques in pathology, which may shed light on prognostic indicators of cancers, and avoid biases introduced by human experience. Purpose: We aim to explore new prognostic indicators of ovarian cancer (OC) patients using the DL framework on WSIs, and provide a valuable approach for OC risk stratification. Methods: We obtained the TCGA-OV dataset from the NIH Genomic Data Commons Data Portal database. The preprocessing of the dataset was comprised of three stages: 1) The WSIs and corresponding clinical data were paired and filtered based on a unique patient ID; 2) a weakly-supervised CLAM WSI-analysis tool was exploited to segment regions of interest; 3) the pre-trained model ResNet50 on ImageNet was employed to extract feature tensors. We proposed an attention-based network to predict a hazard score for each case. Furthermore, all cases were divided into a high-risk score group and a low-risk one according to the median as the threshold value. The multi-omics data of OC patients were used to assess the potential applications of the risk score. Finally, a nomogram based on risk scores and age features was established. Results: A total of 90 WSIs were processed, extracted, and fed into the attention-based network. The mean value of the resulting C-index was 0.5789 (0.5096-0.6053), and the resulting p -value was 0.00845. Moreover, the risk score showed a better prediction ability in the HRD + subgroup. Conclusion: Our deep learning framework is a promising method for searching WSIs, and providing a valuable clinical means for prognosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wu, Zhu, Yang, Cheng, Yang, Gu, Xu, Wu, Shen, Huang and Wang.)

The growing demand for optical anti-counterfeiting technology requires the development of new environmentally-friendly smart materials with single-component, multimodal fluorescence. Herein, Cs 2 ZnBr 4 :0.3Mn 2+ &0.15Cu + , as an efficient multimodal luminescent material with excitation-wavelength-dependent emission is reported. Under 365 nm and 254 nm UV light excitation, Cs 2 ZnBr 4 :Mn 2+ &Cu + emits mutually independent green light at 525 nm and blue light at 470 nm, which origin from the emission of Mn 2+ and the Cu + enhanced self-trapped excitons of Cs 2 ZnBr 4 , respectively. Furthermore, the multiexcitonic emission is applied to anti-counterfeiting applications and information encryption and decryption engineering. This codoped strategy provides a colorful step to expand the new metal halide materials in fluorescent anti-counterfeiting and information encryption and decryption., (© 2022 IOP Publishing Ltd.)

Introduction: Minimally invasive surgery has been widely used in gynecology. The laparoendoscopic single-site surgery (LESS) risk prediction model can provide evidence-based references for preoperative surgical procedure selection., Aim: To determine whether the patients are suitable for LESS and to provide guidance for the clinical operation plan, we aimed to compare the clinical outcomes of LESS and conventional laparoscopic surgery (CLS) in gynecology. We constructed a LESS risk prediction model and predicted surgical conditions for the preoperative evaluation system., Material and Methods: A retrospective analysis was carried out among patients undergoing LESS (n = 1019) and CLS (n = 1055). Various clinical indicators were compared. Multiple machine model algorithms were evaluated. The optimal results were chosen as the model to form the risk prediction model., Results: The LESS group showed advantages in the postoperative 12/24 h visual analog scale and Vancouver scar score compared with the CLS group (p < 0.05). The comparisons in other clinical indicators between the two groups showed that each group had advantages and the difference was statistically significant (p < 0.05), including operative time, estimated blood loss, and hospital stay. We evaluated the predictive value for various models using AUC values of 0.77, 0.77, 0.76, and 0.67 for XGBoost, random forest, GBDT, and logistic regression, respectively. The decision tree model was shown to be the optimal model., Conclusions: LESS can reduce postoperative pain, shorten hospital stay and make scars acceptable. The risk prediction model based on a machine learning algorithm has manifested a high degree of accuracy and can satisfy the doctors' demand for individualized preoperative evaluation and surgical safety in LESS., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2021 Fundacja Videochirurgii.)

COVID-19 has caused numerous infections with diverse clinical symptoms. To identify human genetic variants contributing to the clinical development of COVID-19, we genotyped 1457 (598/859 with severe/mild symptoms) and sequenced 1141 (severe/mild: 474/667) patients of Chinese ancestry. We further incorporated 1401 genotyped and 948 sequenced ancestry-matched population controls, and tested genome-wide association on 1072 severe cases versus 3875 mild or population controls, followed by trans-ethnic meta-analysis with summary statistics of 3199 hospitalized cases and 897,488 population controls from the COVID-19 Host Genetics Initiative. We identified three significant signals outside the well-established 3p21.31 locus: an intronic variant in FOXP4-AS1 (rs1853837, odds ratio OR = 1.28, P = 2.51 × 10 -10 , allele frequencies in Chinese/European AF = 0.345/0.105), a frameshift insertion in ABO (rs8176719, OR = 1.19, P = 8.98 × 10 -9 , AF = 0.422/0.395) and a Chinese-specific intronic variant in MEF2B (rs74490654, OR = 8.73, P = 1.22 × 10 -8 , AF = 0.004/0). These findings highlight an important role of the adaptive immunity and the ABO blood-group system in protection from developing severe COVID-19., (© 2021. The Author(s).)

Wntless (WLS), an evolutionarily conserved multi-pass transmembrane protein, is essential for secretion of Wnt proteins. Wnt-triggered signaling pathways control many crucial life events, whereas aberrant Wnt signaling is tightly associated with many human diseases including cancers. Here, we report the cryo-EM structure of human WLS in complex with Wnt3a, the most widely studied Wnt, at 2.2 Å resolution. The transmembrane domain of WLS bears a GPCR fold, with a conserved core cavity and a lateral opening. Wnt3a interacts with WLS at multiple interfaces, with the lipid moiety on Wnt3a traversing a hydrophobic tunnel of WLS transmembrane domain and inserting into membrane. A β-hairpin of Wnt3a containing the conserved palmitoleoylation site interacts with WLS extensively, which is crucial for WLS-mediated Wnt secretion. The flexibility of the Wnt3a loop/hairpin regions involved in the multiple binding sites indicates induced fit might happen when Wnts are bound to different binding partners. Our findings provide important insights into the molecular mechanism of Wnt palmitoleoylation, secretion and signaling., (© 2021. The Author(s).)

Master splicing regulator MBNL1 shapes large transcriptomic changes that drive cellular differentiation during development. Here we demonstrate that MBNL1 is a suppressor of tumor dedifferentiation. We surveyed MBNL1 expression in matched tumor/normal pairs across The Cancer Genome Atlas and found that MBNL1 was down-regulated in several common cancers. Down-regulation of MBNL1 predicted poor overall survival in breast, lung, and stomach adenocarcinomas and increased relapse and distant metastasis in triple-negative breast cancer. Down-regulation of MBNL1 led to increased tumorigenic and stem/progenitor-like properties in vitro and in vivo. A discrete set of alternative splicing events (ASEs) are shared between MBNL1 -low cancers and embryonic stem cells including a MAP2K7∆ exon2 splice variant that leads to increased stem/progenitor-like properties via JNK activation. Accordingly, JNK inhibition is capable of reversing MAP2K7 ∆exon2-driven tumor dedifferentiation in MBNL1-low cancer cells. Our work elucidates an alternative-splicing mechanism that drives tumor dedifferentiation and identifies biomarkers that predict enhanced susceptibility to JNK inhibition., Competing Interests: Competing interest statement: D.R is an inventor on a patent “Stratification of Cancer Patients by MBNL1 and MAP2K7Δexon2 Expression for Susceptibility to JNK Inhibition” filed in the Singapore patent office, Provisional Application No. 10201910208U. D.M.E is the founder, director, and CEO of Black Diamond Therapeutics and a consultant to Engine Bioscience in areas unrelated to this manuscript., (Copyright © 2020 the Author(s). Published by PNAS.)

The gut microbiota represents a huge community of microorganisms that play essential roles in immune modulation and homeostasis maintenance. Microbiota transplantation is an important approach to prevent and treat disease as it can inhibit pathogen colonization and positively modulate bacterial composition. However, the development of oral bacterial therapeutics has been restricted by low bioavailability and limited retention in the gastrointestinal tract. Here, we report a simple yet highly efficient method to coat gut microbes via biointerfacial supramolecular self-assembly. Coating can be performed within 15 min by simply vortexing with biocompatible lipids. Bacteria coated with an extra self-assembled lipid membrane exhibit significantly improved survival against environmental assaults and almost unchanged viability and bioactivity. We demonstrate their enhanced efficacies in oral delivery and treatment using two murine models of colitis. We suggest that biointerfacial supramolecular self-assembly may provide a unique platform to generate advanced bacterial therapeutics for the treatment of various diseases.

Bacteria have been extensively utilized for bioimaging, diagnosis and therapy given their unique characteristics including genetic manipulation, rapid proliferation and disease site targeting specificity. However, clinical translation of bacteria for these applications has been largely restricted by their unavoidable side effects and low treatment efficacies. Engineered bacteria for biomedical applications ideally need to generate only a low inflammatory response, show slow elimination by macrophages, low accumulation in normal organs, and almost unchanged inherent bioactivities. Here we describe a set of stealth bacteria, cell membrane coated bacteria (CMCB), meeting these requirement. Our findings are supported by evaluation in multiple mice models and ultimately demonstrate the potential of CMCB to serve as efficient tumor imaging agents. Stealth bacteria wrapped up with cell membranes have the potential for a myriad of bacterial-mediated biomedical applications.

Hemoglobin (Hb) is a family of proteins in red blood cells responsible for oxygen transport and vulnerable for oxidative damage. Hemoglobin δ subunit (HBD), a member of Hb family, is normally expressed by cells of erythroid lineage. Expression of Hb genes has been previously reported in nonerythroid and hematopoietic stem cells. Here, we report that Hb and HBD can be degraded via REG γ proteasome in hemopoietic tissues and nonerythroid cells. For this purpose, bone marrow, liver, and spleen hemopoietic tissues from REGγ +/+ and REGγ -/- mice and stable REG γ knockdown cells were evaluated for the degradation of Hb and HBD via REG γ . Western blot and immunohistochemical analyses exhibited downregulation of Hb in REG γ wild-type mouse tissues. This was validated by dynamic analysis following blockade of de novo synthesis of proteins with CHX. Degradation of HBD only occurred in REG γ WT cells but not in REG γ N151Y, a dominant-negative REG γ mutant cell. Notably, downregulation of HBD was found in HeLa shN cells with stimulation of phenylhydrazine, an oxidation inducer, suggesting that the REG γ proteasome may target oxidatively damaged Hbs. In conclusion, our findings provide important implications for the degradation of Hb and HBD in hemopoietic tissues and nonerythroid cells via the REG γ proteasome.