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Abstract Ulcerative colitis (UC) is a debilitating inflammatory bowel disease characterized by intestinal inflammation, barrier dysfunction, and dysbiosis, with limited treatment options available. This study systematically investigates the therapeutic potential of a synbiotic composed of galactooligosaccharides (GOS) and Limosilactobacillus reuteri in a murine model of colitis, revealing that GOS and L. reuteri synergistically protect against intestinal inflammation and barrier dysfunction by promoting the synthesis of pentadecanoic acid, an odd-chain fatty acid, from Bacteroides acidifaciens. Notably, the synbiotic, B. acidifaciens, and pentadecanoic acid are each capable of suppressing intestinal inflammation and enhancing tight junction by inhibiting NF-κB activation. Furthermore, similar reduction in B. acidifaciens and pentadecanoic acid levels are also observed in the feces from both human UC patients and lipopolysaccharide-induced intestinal inflammation in pigs. Our findings elucidate the protective mechanism of the synbiotic and highlight its therapeutic potential, along with B. acidifaciens and pentadecanoic acid, for UC and other intestinal inflammatory disorders.

Abstract Background Surgery for adnexal mass does occur in pregnant women and therefore the choice of surgery during pregnancy needs to be carefully considered and studied. This study aimed to evaluate the safety and feasibility of Laparo-endoscopic Single-site Surgery (LESS) for adnexal mass during pregnancy and investigate the perioperative condition, pregnancy complications, and obstetric outcomes of operative women during pregnancy. Methods This study retrospectively collected medical records and surgery videos of 20 pregnant women who underwent LESS for adnexal mass between November 2019 and January 2022. Baseline characteristics, operative-related variables, and pregnancy outcomes were followed up. Results LESS for adnexal mass was successfully performed in 20 pregnant women, with very satisfactory surgery outcomes reported in all cases. The average gestational age at operation was 15+2 weeks (range, 5+1- 25+4 weeks). The median operative time was 80.8 min (range, 40 -185 min) and the average operative bleeding was 28.0 ml (range, 10–50 ml). The average VAS of 24 h postoperatively was 1 (range, 0–2), and the average length of hospital stay was 5.15 days (range, 3–7 days). All these women delivered a healthy newborn at full term except 1 woman induced abortion for her own reasons at 16+5 weeks gestational age (GA). The average GA of delivery was 39+1 weeks (range, 37–40+1 weeks), the average birth weight was 3228.95 g (range, 2740–3930 g), and the average Apgar score at 5 min was 9.95 (range, 9–10). Conclusions LESS for adnexal mass is safe and feasible for pregnant women.

Abstract Pyroelectric (PE) detection technologies have attracted extensive attention due to the cooling-free, bias-free, and broadband properties. However, the PE signals are generated by the continuous energy conversion processes from light, heat, to electricity, normally leading to very slow response speeds. Herein, we design and fabricate a PE detector which shows extremely fast response in near-infrared (NIR) band by combining with the inhomogeneous plasmonic metasurface. The plasmonic effect dramatically accelerates the light-heat conversion process, unprecedentedly improving the NIR response speed by 2−4 orders of magnitude to 22 μs, faster than any reported infrared (IR) PE detector. We also innovatively introduce the concept of time resolution into the field of PE detection, which represents the detector’s ability to distinguish multiple fast-moving targets. Furthermore, the spatially inhomogeneous design overcomes the traditional narrowband constraint of plasmonic systems and thus ensures a wideband response from visible to NIR. This study provides a promising approach to develop next-generation IR PE detectors with ultrafast and broadband responses.

Making accurate predictions of the construction cost is essential for ensuring the smooth implementation of projects and guaranteeing economic benefits. The problem to be studied in this article is how to predict construction project costs accurately. The related factors affecting construction project costs are briefly introduced in this paper. A back-propagation neural network (BPNN) was proposed to predict construction engineering costs, and the AdaBoost algorithm was used to improve it. Then, simulation experiments were carried out. It was found that the Adaboost-BPNN algorithm converged to stability faster, and the mean square error was smaller (10-5) when it was stable. Compared with the support vector machine and traditional BPNN algorithms, the AdaBoost-BPNN algorithm had better goodness of fit (0.787) and provided more accurate prediction results for construction engineering costs (mean average error: 0.467, root-mean-square error: 1.118). The novelty of this article lies in utilizing AdaBoost to combine multiple weak predictors into a strong predictor, thereby enhancing the performance of the BPNN algorithm. The contribution lies in improving the predictive performance of the BPNN through the combination principle of AdaBoost, providing an effective reference for accurate cost prediction in construction engineering.

Abstract Spacetime wormholes can provide non-perturbative contributions to the gravitational path integral that make the actual number of states e S in a gravitational system much smaller than the number of states e S p $$ {e}^{S_{\textrm{p}}} $$ predicted by perturbative semiclassical effective field theory. The effects on the physics of the system are naturally profound in contexts in which the perturbative description actively involves N = O(e S ) of the possible e S p $$ {e}^{S_{\textrm{p}}} $$ perturbative states; e.g., in late stages of black hole evaporation. Such contexts are typically associated with the existence of non-trivial quantum extremal surfaces. However, by forcing a simple topological gravity model to evolve in time, we find that such effects can also have large impact for N ≪ e S (in which case no quantum extremal surfaces can arise). In particular, even for small N, the insertion of generic operators into the path integral can cause the non-perturbative time evolution to differ dramatically from perturbative expectations. On the other hand, this discrepancy is small for the special case where the inserted operators are non-trivial only in a subspace of dimension D ≪ e S . We thus study this latter case in detail. We also discuss potential implications for more realistic gravitational systems.

Abstract The CRISPR/Cas9 system has shown great potential for treating human genetic diseases through gene therapy. However, there are concerns about the safety of this system, specifically related to the use of guide-free Cas9. Previous studies have shown that guide-free Cas9 can induce genomic instability in vitro. However, the in vivo safety risks associated with guide-free Cas9 have not been evaluated, which is necessary for the development of gene therapy in clinical settings. In this study, we used doxycycline-inducible Cas9-expressing pigs to evaluate the safety risks of guide-free Cas9 in vivo. Our findings demonstrated that expression of guide-free Cas9 could induce genomic damages and transcriptome changes in vivo. The severity of the genomic damages and transcriptome changes were correlate with the expression levels of Cas9 protein. Moreover, prolonged expression of Cas9 in pigs led to abnormal phenotypes, including a significant decrease in body weight, which may be attributable to genomic damage-induced nutritional absorption and metabolic dysfunction. Furthermore, we observed an increase in whole-genome and tumor driver gene mutations in pigs with long-term Cas9 expression, raising the risk of tumor occurrence. Our in vivo evaluation of guide-free Cas9 in pigs highlights the necessity of considering and monitoring the detrimental effects of Cas9 alone as genome editing via the CRISPR/Cas9 system is implemented in clinical gene therapy. This research emphasizes the importance of further study and implementation of safety measures to ensure the successful and safe application of the CRISPR/Cas9 system in clinical practice.

Abstract Platinum-based chemotherapy is the standard postoperative adjuvant treatment for ovarian cancer (OC). Despite the initial response to chemotherapy, 85% of advanced OC patients will have recurrent disease. Relapsed disease and platinum resistance are the major causes of death in OC patients. In this study, we compared the global regulation of alternative polyadenylation (APA) in platinum-resistant and platinum-sensitive tissues of OC patients by analyzing a set of single-cell RNA sequencing (scRNA-seq) data from public databases and found that platinum-resistant patients exhibited global 3’ untranslated region (UTR) shortening due to the different usage of polyadenylation sites (PASs). The APA regulator CSTF3 was the most significantly upregulated gene in epithelial cells of platinum-resistant OC. CSTF3 knockdown increased the sensitivity of OC cells to platinum. The lncRNA NEAT1 has two isoforms, short (NEAT1_1) and long (NEAT1_2) transcript, because of the APA processing in 3’UTR. We found that CSTF3 knockdown reduced the usage of NEAT1 proximal PAS to lengthen the transcript and facilitate the expression of NEAT1_2. Downregulation of the expression of NEAT1 (NEAT1_1/_2), but not only NEAT1_2, also increased the sensitivity of OC cells to platinum. Overexpressed NEAT1_1 reversed the platinum resistance of OC cells after knocking down CSTF3 expression. Furthermore, downregulated expression of CSTF3 and NEAT1_1, rather than NEAT1_2, was positively correlated with inactivation of the PI3K/AKT/mTOR pathway in OC cells. Together, our findings revealed a novel mechanism of APA regulation in platinum-resistant OC. CSTF3 directly bound downstream of the NEAT1 proximal PAS to generate the short isoform NEAT1_1 and was conducive to platinum resistance, which provides a potential biomarker and therapeutic strategy for platinum-resistant OC patients.

Abstract We consider four-dimensional Euclidean gravity in a finite cavity. Dirichlet conditions do not yield a well-posed elliptic system, and Anderson has suggested boundary conditions that do. Here we point out that there exists a one-parameter family of boundary conditions, parameterized by a constant p, where a suitably Weyl rescaled boundary metric is fixed, and all give a well-posed elliptic system. Anderson and Dirichlet boundary conditions can be seen as the limits p → 0 and ∞ of these. Focussing on static Euclidean solutions, we derive a thermodynamic first law. Restricting to a spherical spatial boundary, the infillings are flat space or the Schwarzschild solution, and have similar thermodynamics to the Dirichlet case. We consider smooth Euclidean fluctuations about the flat space saddle; for p > 1/6 the spectrum of the Lichnerowicz operator is stable — its eigenvalues have positive real part. Thus we may regard large p as a regularization of the ill-posed Dirichlet boundary conditions. However for p < 1/6 there are unstable modes, even in the spherically symmetric and static sector. We then turn to Lorentzian signature. For p < 1/6 we may understand this spherical Euclidean instability as being paired with a Lorentzian instability associated with the dynamics of the boundary itself. However, a mystery emerges when we consider perturbations that break spherical symmetry. Here we find a plethora of dynamically unstable modes even for p > 1/6, contrasting starkly with the Euclidean stability we found. Thus we seemingly obtain a system with stable thermodynamics, but unstable dynamics, calling into question the standard assumption of smoothness that we have implemented when discussing the Euclidean theory.

Abstract Photodetectors based on 2D hetero‐bilayers can overcome the bandgap limitations of individual 2D monolayers and operate at relatively long wavelengths. However, ultra‐low light absorptions within hetero‐bilayers result in extremely weak photoresponsivity. Here, an infrared photodetector based on the MoS2/MoTe2 type‐II hetero‐bilayer is demonstrated to reach a photoresponsivity of 0.55 A W−1 at 1550 nm, well beyond energy band cut‐offs of monolayer MoS2 and MoTe2, primarily resulted from the photogating effect. Raman and photoluminescence (PL) spectroscopy reveal strong interlayer couplings in the hetero‐bilayer, and a broad PL peak around 1550 nm is observed that is ascribed to interlayer transitions of carriers. The photodetector showcases a broadband detection capability from 1100 to 1700 nm, with a peak at 1550 nm corresponding to the interlayer absorption. Electrical characterization of the hetero‐bilayer‐based field‐effect transistor and kelvin probe force microscopy reveal efficient interlayer hole transfer. The highly responsive MoS2/MoTe2 infrared photodetector offers a large photo‐gain of ≈103 and a time constant of 130 ms. The research illuminates how interlayer transitions affect 2D hetero‐bilayer‐based photodetectors and advances the utilization of layered semiconductor heterostructures.

Abstract In cancer treatment, therapeutic strategies that integrate tumor-specific characteristics (i.e., precision oncology) are widely implemented to provide clinical benefits for cancer patients. Here, through in-depth integration of tumor transcriptome and patients’ prognoses across cancers, we investigated dysregulated and prognosis-associated genes and catalogued such important genes in a cancer type-dependent manner. Utilizing the expression matrices of these genes, we built models to quantitatively evaluate the malignant levels of tumors across cancers, which could add value to the clinical staging system for improved prediction of patients’ survival. Furthermore, we performed a transcriptome-based molecular subtyping on hepatocellular carcinoma, which revealed three subtypes with significantly diversified clinical outcomes, mutation landscapes, immune microenvironment, and dysregulated pathways. As tumor transcriptome was commonly profiled in clinical practice with low experimental complexity and cost, this work proposed easy-to-perform approaches for practical clinical promotion towards better healthcare and precision oncology of cancer patients.

Abstract Background Many efforts have been made to improve the precision of Cas9-mediated gene editing through increasing knock-in efficiency and decreasing byproducts, which proved to be challenging. Results Here, we have developed a human exonuclease 1-based genome-editing tool, referred to as exonuclease editor. When compared to Cas9, the exonuclease editor gave rise to increased HDR efficiency, reduced NHEJ repair frequency, and significantly elevated HDR/indel ratio. Robust gene editing precision of exonuclease editor was even superior to the fusion of Cas9 with E1B or DN1S, two previously reported precision-enhancing domains. Notably, exonuclease editor inhibited NHEJ at double strand breaks locally rather than globally, reducing indel frequency without compromising genome integrity. The replacement of Cas9 with single-strand DNA break-creating Cas9 nickase further increased the HDR/indel ratio by 453-fold than the original Cas9. In addition, exonuclease editor resulted in high microhomology-mediated end joining efficiency, allowing accurate and flexible deletion of targeted sequences with extended lengths with the aid of paired sgRNAs. Exonuclease editor was further used for correction of DMD patient-derived induced pluripotent stem cells, where 30.0% of colonies were repaired by HDR versus 11.1% in the control. Conclusions Therefore, the exonuclease editor system provides a versatile and safe genome editing tool with high precision and holds promise for therapeutic gene correction.

Abstract Due to the conformal factor problem, the definition of the Euclidean gravitational path integral requires a non-trivial choice of contour. The present work examines a generalization of a recently proposed rule-of-thumb [1] for selecting this contour at quadratic order about a saddle. The original proposal depended on the choice of an indefinite-signature metric on the space of perturbations, which was taken to be a DeWitt metric with parameter α = – 1. This choice was made to match previous results, but was otherwise admittedly ad hoc. To begin to investigate the physics associated with the choice of such a metric, we now explore contours defined using analogous prescriptions for α ≠ – 1. We study such contours for Euclidean gravity linearized about AdS-Schwarzschild black holes in reflecting cavities with thermal (canonical ensemble) boundary conditions, and we compare path-integral stability of the associated saddles with thermodynamic stability of the classical spacetimes. While the contour generally depends on the choice of DeWitt parameter α, the precise agreement between these two notions of stability found at α = – 1 continues to hold over the finite interval (– 2, – 2/d), where d is the dimension of the bulk spacetime. This agreement manifestly fails for α > – 2/d when the DeWitt metric becomes positive definite. However, we also find dramatic failures for α < – 2 that correlate with breakdowns of the de Donder-like gauge condition defined by α, and at which the relevant fluctuation operator fails to be diagonalizable. This provides criteria that may be useful in predicting metrics on the space of perturbations that give physically-useful contours in more general settings. Along the way, we also identify an interesting error in [1], though we show this error to be harmless.

Abstract Background Prime editing enables precise base substitutions, insertions, and deletions at targeted sites without the involvement of double-strand DNA breaks or exogenous donor DNA templates. However, the large size of prime editors (PEs) hampers their delivery in vivo via adeno-associated virus (AAV) due to the viral packaging limit. Previously reported split PE versions provide a size reduction, but they require intricate engineering and potentially compromise editing efficiency. Results Herein, we present a simplified split PE named as CC-PE, created through non-covalent recruitment of reverse transcriptase to the Cas9 nickase via coiled-coil heterodimers, which are widely used in protein design due to their modularity and well-understood sequence-structure relationship. We demonstrate that the CC-PE maintains or even surpasses the efficiency of unsplit PE in installing intended edits, with no increase in the levels of undesired byproducts within tested loci amongst a variety of cell types (HEK293T, A549, HCT116, and U2OS). Furthermore, coiled-coil heterodimers are used to engineer SpCas9-NG-PE and SpRY-PE, two Cas9 variants with more flexible editing scope. Similarly, the resulting NG-CC-PE and SpRY-CC-PE also achieve equivalent or enhanced efficiency of precise editing compared to the intact PE. When the dual AAV vectors carrying CC-PE are delivered into mice to target the Pcsk9 gene in the liver, CC-PE enables highly efficient precise editing, resulting in a significant reduction of plasma low-density lipoprotein cholesterol and total cholesterol. Conclusions Our innovative, modular system enhances flexibility, thus potentially facilitating the in vivo applicability of prime editing.

Abstract 5-Methylcytosine (m5C) is a common RNA modification that modulates gene expression at the posttranscriptional level, but the crosstalk between m5C RNA modification and biomolecule condensation, as well as transcription factor-mediated transcriptional regulation, in ovarian cancer, is poorly understood. In this study, we revealed that the RNA methyltransferase NSUN2 facilitates mRNA m5C modification and forms a positive feedback regulatory loop with the transcription factor E2F1 in ovarian cancer. Specifically, NSUN2 promotes m5C modification of E2F1 mRNA and increases its stability, and E2F1 binds to the NSUN2 promoter, subsequently reciprocally activating NSUN2 transcription. The RNA binding protein YBX1 functions as the m5C reader and is involved in NSUN2-mediated E2F1 regulation. m5C modification promotes YBX1 phase separation, which upregulates E2F1 expression. In ovarian cancer, NSUN2 and YBX1 are amplified and upregulated, and higher expression of NSUN2 and YBX1 predicts a worse prognosis for ovarian cancer patients. Moreover, E2F1 transcriptionally regulates the expression of the oncogenes MYBL2 and RAD54L, driving ovarian cancer progression. Thus, our study delineates a NSUN2-E2F1-NSUN2 loop regulated by m5C modification in a manner dependent on YBX1 phase separation, and this previously unidentified pathway could be a promising target for ovarian cancer treatment.

BackgroundThe rising incidence of drug abuse among pregnant women has rendered neonatal opioid withdrawal syndrome a significant global health concern.MethodsDatabases including PubMed, Web of Science, the Cochrane Library, Embase, Elton B. Stephens. Company (EBSCO), China National Knowledge Infrastructure (CNKI), and Wanfang were searched for comparative studies of the Eat, Sleep, Console model vs. traditional assessment tools for neonatal opioid withdrawal syndrome. Two reviewers conducted literature searches, screened according to the inclusion criteria, extracted data, and independently verified accuracy. All meta-analyses were conducted using Review Manager Version 5.4.ResultsIn total, 18 studies involving 4,639 neonates were included in the meta-analysis. The Eat, Sleep, Console model demonstrated superior outcomes in assessing neonatal opioid withdrawal syndrome, significantly reducing the need for pharmacological treatment [risk ratio = 0.44, 95% confidence interval (CI) = 0.34–0.56, P

Summary: Background: Premature ovarian failure (POF) is a prevalent and severe condition that impairs female health but there is currently no effective treatment available to restore ovarian function. Human amniotic epithelial cells (hAECs) exhibit ovarian protection in pre-clinical models. Thus, we conducted a single-arm, phase 1 clinical trial to assess the safety and efficacy of allogenic hAECs in treating POF. Methods: A total of 35 patients received 6 × 107 hAECs via ovarian artery and completed a five-month follow-up from December 30, 2020 to January 31, 2022. The follow-up assessments were conducted at various intervals after hAECs treatment, including one month (Visit-1, V-1), three months (Visit-2, V-2), and five months (Visit-3, V-3) post-treatment. The primary endpoints were incidence of adverse events (AEs), and clinically significant laboratory abnormalities. Secondary endpoints included evaluation of transvaginal ultrasound results, sex hormone levels, Menopausal Quality of Life (MENQOL) questionnaire, as well as reproductive indicators. This trial was registered at www.clinicaltrials.gov as NCT02912104. Findings: No serious AEs were observed throughout the five-month follow-up period. The most common AE was hematoma (7/35, 20.00%), and other AEs include pelvic pain (4/35, 11.43%), fever (2/35, 5.71%), anaphylaxis (2/35, 5.71%), and hepatotoxicity (1/35, 2.86%). After hAECs transplantation (hAECT), significant improvements were observed in the levels of endometrial thickness, left ovarian volume, sex hormones (follicle-stimulating hormone (FSH) and estradiol (E2)), and MENQOL scores in all patients during the five-month follow-up period. Among them, 13 participants (37.14%) experienced spontaneous menstrual bleeding, and 20.00% (7/35) reported more than one regular menstrual bleeding post-hAECT. In this response group, significant improvements were observed in endometrial thickness, left ovarian volume, levels of FSH, E2, anti-Müllerian hormone (AMH), and MENQOL scores one month after hAECT in comparison to pre-hAECT. Interpretation: hAECT via ovarian artery is safe, well-tolerated and temporarily ameliorates endometrial thickness, ovarian size, hormone levels, and menopausal symptoms in POF patients. Further randomized controlled trial of hAECs with longer follow-up period and a larger sample size is warranted. Funding: National Natural Science Foundation of China (No. 82271664), the Interdisciplinary Program of Shanghai Jiao Tong University (YG2022ZD028), the Shanghai Municipal Health Committee (202240345), Shanghai Key Laboratory of Embryo Original Diseases (No. Shelab2022ZD01), Shanghai Municipal Education Commission (No. 20152236), and National Key Research and Development Program of China (No. 2018YFC1004802), Shanghai Clinical Research Center for Cell Therapy, China (No. 23J41900100).

De novo drug design is crucial in advancing drug discovery, which aims to generate new drugs with specific pharmacological properties. Recently, deep generative models have achieved inspiring progress in generating drug-like compounds. However, the models prioritize a single target drug generation for pharmacological intervention, neglecting the complicated inherent mechanisms of diseases, and influenced by multiple factors. Consequently, developing novel multi-target drugs that simultaneously target specific targets can enhance anti-tumor efficacy and address issues related to resistance mechanisms. To address this issue and inspired by Generative Pre-trained Transformers (GPT) models, we propose an upgraded GPT model with generative adversarial imitation learning for multi-target molecular generation called MTMol-GPT. The multi-target molecular generator employs a dual discriminator model using the Inverse Reinforcement Learning (IRL) method for a concurrently multi-target molecular generation. Extensive results show that MTMol-GPT generates various valid, novel, and effective multi-target molecules for various complex diseases, demonstrating robustness and generalization capability. In addition, molecular docking and pharmacophore mapping experiments demonstrate the drug-likeness properties and effectiveness of generated molecules potentially improve neuropsychiatric interventions. Furthermore, our model's generalizability is exemplified by a case study focusing on the multi-targeted drug design for breast cancer. As a broadly applicable solution for multiple targets, MTMol-GPT provides new insight into future directions to enhance potential complex disease therapeutics by generating high-quality multi-target molecules in drug discovery.

Introduction: Galactooligosaccharides (GOS) are lactogenic prebiotics that exert health benefits by stimulating the growth of different Lactobacillus strains in the gastrointestinal (GI) tract. Objectives: This study aimed to investigate the mechanism of action of different GOS-enriched lactobacilli in intestinal health. Methods: Piglets and mice were supplemented with GOS to identify specific enrichment of Lactobacillus. The protective effects of individual GOS-enriched lactobacilli were investigated in Salmonella-infected mice. Macrophage depletion and transcriptome analysis were further performed to assess the involvement of macrophages and the underlying mechanisms of individual lactobacilli. An in vitro cell co-culture system was also used to evaluate the anti-adhesive and anti-invasive activities of lactobacilli against Salmonella in epithelial cells. Results: GOS markedly increased the relative abundance of three lactobacilli including L. delbrueckii, L. johnsonii, and L. reuteri in both piglets and mice. Supplementation with GOS further alleviated Salmonella infection in mice. L. delbrueckii (ATCC®BAA 365™), but not L. johnsonii or L. reuteri, enhanced propionate production in the intestinal tract and ameliorated Salmonella-induced intestinal inflammation and barrier dysfunction by suppressing the JAK2-STAT3 signaling and M1 macrophage polarization. L. johnsonii (BNCC 186110), on the other hand, inhibited Salmonella adhesion and invasion of epithelial cells through competitive exclusion. However, L. reuteri (BNCC 186135) failed to protect mice against Salmonella infection. Conclusion: GOS-enriched lactobacilli show a differential role in protecting against Salmonella-induced intestinal barrier dysfunction and inflammation. Our results provide novel insights into the mechanism of action of GOS and individual Lactobacillus strains in the control and prevention of intestinal inflammatory disorders.

Rheumatoid arthritis (RA) is an autoimmune disease with a complex etiology. Monocyte-derived macrophages (MDMs) infiltration are associated with RA severity. We have reported the deletion of G-protein-coupled receptor kinase 2 (GRK2) reprograms macrophages toward an anti-inflammatory phenotype by recovering G-protein-coupled receptor signaling. However, as more GRK2-interacting proteins were discovered, the GRK2 interactome mechanisms in RA have been understudied. Thus, in the collagen-induced arthritis mouse model, we performed genetic GRK2 deletion using GRK2f/fLyz2-Cre+/− mice. Synovial inflammation and M1 polarization were improved in GRK2f/fLyz2-Cre+/− mice. Supporting experiments with RNA-seq and dual-luciferase reporter assays identified peroxisome proliferator-activated receptor γ (PPARγ) as a new GRK2-interacting protein. We further confirmed that fms-related tyrosine kinase 1 (Flt-1), which promoted macrophage migration to induce angiogenesis, was inhibited by GRK2-PPARγ signaling. Mechanistically, excess GRK2 membrane recruitment in CIA MDMs reduced the activation of PPARγ ligand-binding domain and enhanced Flt-1 transcription. Furthermore, the treatment of mice with GRK2 activity inhibitor resulted in significantly diminished CIA pathology, Flt-1+ macrophages induced-synovial inflammation, and angiogenesis. Altogether, we anticipate to facilitate the elucidation of previously unappreciated details of GRK2-specific intracellular signaling. Targeting GRK2 activity is a viable strategy to inhibit MDMs infiltration, affording a distinct way to control joint inflammation and angiogenesis of RA.

With the rapid advancement of deep learning technologies, computer vision has shown immense potential in retail automation. This paper presents a novel self-checkout system for retail based on an improved YOLOv10 network, aimed at enhancing checkout efficiency and reducing labor costs. We propose targeted optimizations for the YOLOv10 model, incorporating the detection head structure from YOLOv8, which significantly improves product recognition accuracy. Additionally, we develop a post-processing algorithm tailored for self-checkout scenarios, to further enhance the application of the system. Experimental results demonstrate that our system outperforms existing methods in both product recognition accuracy and checkout speed. This research not only provides a new technical solution for retail automation but offers valuable insights into optimizing deep learning models for real-world applications.

Abstract Conditional gene regulation systems can control gene expression in predefined tissues or organs at a desired time. Site‐specific recombinase systems and chemically induced gene expression systems are the two most widely used approaches for creating genetically modified (GM) animals with conditional regulation of gene expression. Generation of GM pigs with controllable elements, usually involving multiple gene editing, used to be a major challenge due to a lack of germ line‐competent pluripotent stem cells. With the emergence of artificial endonuclease‐mediated gene editors, a variety of GM pigs with recombinase‐specific recognition elements or chemically induced elements for conditional regulation of gene expression have been generated by the combination of site‐directed knock‐in of somatic cells and somatic cell nuclear transfer technology, allowing conditional deletion of endogenous genes or overexpression of exogenous genes in pigs. These inducible tool pig models will greatly facilitate the production of GM pigs and broaden the applications of transgenic pigs in biomedicine and agriculture fields. In this paper, we review the progress in the construction and application of pigs with controllable elements using gene editing techniques.

Abstract Background High-copper diets have been widely used to promote growth performance of pigs, but excess copper supplementation can also produce negative effects on ecosystem stability and organism health. High-copper supplementation can damage the intestinal barrier and disturb the gut microbiome community. However, the specific relationship between high-copper-induced intestinal damage and gut microbiota or its metabolites is unclear. Objective Using fecal microbiota transplantation and metagenomic sequencing, responses of colonic microbiota to a high-copper diet was profiled. In addition, via comparison of specific bacteria and its metabolites rescue, we investigated a network of bacteria-metabolite interactions involving conversion of specific metabolites as a key mechanism linked to copper-induced damage of the colon. Results High copper induced colonic damage, Lactobacillus extinction, and reduction of SCFA (acetate and butyrate) concentrations in pigs. LefSe analysis and q-PCR results confirmed the extinction of L. johnsonii. In addition, transplanting copper-rich fecal microbiota to ABX mice reproduced the gut characteristics of the pig donors. Then, L. johnsonii rescue could restore decreased SCFAs (mainly acetate and butyrate) and colonic barrier damage including thinner mucus layer, reduced colon length, and tight junction protein dysfunction. Given that acetate and butyrate concentrations exhibited a positive correlation with L. johnsonii abundance, we investigated how L. johnsonii exerted its effects by supplementing acetate and butyrate. L. johnsonii and butyrate administration but not acetate could correct the damaged colonic barrier. Acetate administration had no effects on butyrate concentration, indicating blocked conversion from acetate to butyrate. Furthermore, L. johnsonii rescue enriched a series of genera with butyrate-producing ability, mainly Lachnospiraceae NK4A136 group. Conclusions For the first time, we reveal the microbiota-mediated mechanism of high-copper-induced colonic damage in piglets. A high-copper diet can induce extinction of L. johnsonii which leads to colonic barrier damage and loss of SCFA production. Re-establishment of L. johnsonii normalizes the SCFA-producing pathway and restores colonic barrier function. Mechanistically, Lachnospiraceae NK4A136 group mediated conversion of acetate produced by L. johnsonii to butyrate is indispensable in the protection of colonic barrier function. Collectively, these findings provide a feasible mitigation strategy for gut damage caused by high-copper diets. Video Abstract

Rapid urbanization is universally acknowledged to degrade ecosystem services, posing significant threats to human well-being. However, the effects of urban shrinkage, a global phenomenon and a counterpart to urbanization, on ecosystem services (ESs) remain unclear. This study focuses on China’s Rust Belt during the period from 2000 to 2020, constructing a comprehensive analytical framework based on long-term remote sensing data to reveal the temporal and spatial patterns of ESs and their associations with cities experiencing varying degrees of shrinkage. It employs a random forest (RF) model and a Shapley additive explanation (SHAP) model to measure and visualize the significance and thresholds of socioeconomic factors influencing changes in ESs. Our findings highlight the following: (1) Since 2010, the three provinces of Northeast China (TPNC) have begun to shrink comprehensively, with the degree of shrinkage intensifying over time. Resource-based cities have all experienced contraction. (2) Regional urban shrinkage has been found to enhance the overall provision capacity of ESs, with the most significant improvements in cities undergoing continuous shrinkage. (3) The impact of the same socioeconomic drivers varies across cities with different levels of shrinkage; increasing green-space ratios and investing more in public welfare have been identified as effective measures to enhance ESs. (4) Threshold analysis indicates that the stability of the tertiary sector’s proportion is critically important for enhancing ESs in cities undergoing intermittent shrinkage. An increase of 10% to 15% in this sector can allow continuously shrinking cities to balance urban development with ecological improvements. This research highlights the positive aspects of urban shrinkage, demonstrating its ability to enhance the provision capacity of ESs. It offers new insights into the protection and management of regional ecosystems and the urban transformation of the three eastern provinces.

Hybrid rice needs to prevent lodging due to excessive grain weight during maturity, which can lead to yield loss, grain quality deterioration and difficulty in harvesting. Breeding excellent parents (restorer and male-sterile lines) is the foundation for cultivating lodging-resistant hybrid rice. However, there is still limited information about restorers with improved lodging resistance. To identify a new restorer with significantly enhanced resistance to lodging, the restorer line Huazhan, which has been used for many years in hybrid rice breeding in China, was used as the control, to evaluate the lodging resistance of the new restorer R382. A two-year field experiment was executed to investigate the difference on lodging-related traits of the basal two internodes above-ground, such as out diameters of stems with or without leaf sheath (DWS, DWOS), culm thickness (CT), the section modulus (SM), bending stress (BS), and bending moment at break (M). The results indicated that DWS, CT, BS, M of R382 was at least 19.9%, 13.3%, 36.5% and 52.6% higher than that of Huazhan. However, the negative indicator lodging index of R382 was over 17.5% lower. The number and area of vascular bundles, and the contents of the chemical components of the cell wall including cellulose, lignin, and hemicellulose, together with the accumulation of starch granules, were significantly greater in R382. Furthermore, in the basal stems during the jointing stage, a series of genes that promote cell wall formation exhibited significantly higher expression levels in R382. Meanwhile, there was no significant difference in the yield of R382 and Huazhan. Thus, this new restorer could be a valuable donor in the future hybrid rice breeding programs for improving lodging resistance.

Abstract Studies on behavioral oscillations demonstrate that visual sensitivity fluctuates over time and visual processing varies periodically, mirroring neural oscillations at the same frequencies. Do these behavioral oscillations reflect fixed and relatively automatic sensory sampling, or top-down processes such as attention or predictive coding? To disentangle these theories, the current study used a dual-target rapid serial visual presentation paradigm, where participants indicated the gender of a face target embedded in streams of distractors presented at 30 Hz. On critical trials, two identical targets were presented with varied stimulus onset asynchrony from 200 to 833 ms. The target was either familiar or unfamiliar faces, divided into different blocks. We found a 4.6 Hz phase-coherent fluctuation in gender discrimination performance across both trial types, consistent with previous reports. In addition, however, we found an effect at the alpha frequency, with behavioral oscillations in the familiar blocks characterized by a faster high-alpha peak than for the unfamiliar face blocks. These results are consistent with the combination of both a relatively stable modulation in the theta band and faster modulation of the alpha oscillations. Therefore, the overall pattern of perceptual sampling in visual perception may depend, at least in part, on task demands. Protocol registration The stage 1 protocol for this Registered Report was accepted in principle on 16/08/2022. The protocol, as accepted by the journal, can be found at: https://doi.org/10.17605/OSF.IO/A98UF .

Abstract Background Clinically, although chemotherapy is one of the most commonly used methods of treating tumors, chemotherapeutic drugs can induce autophagic flux and increase tumor cell resistance, leading to drug tolerance. Therefore, theoretically, inhibiting autophagy may improve the efficacy of chemotherapy. The discovery of autophagy regulators and their potential application as adjuvant anti-cancer drugs is of substantial importance. In this study, we clarified that Fangjihuangqi Decoction (FJHQ, traditional Chinese medicine) is an autophagy inhibitor, which can synergistically enhance the effect of cisplatin and paclitaxel on non-small cell lung cancer (NSCLC) cells. Methods We observed the changes of autophagy level in NSCLC cells under the effect of FJHQ, and verified the level of the autophagy marker protein and cathepsin. Apoptosis was detected after the combination of FJHQ with cisplatin or paclitaxel, and NAC (ROS scavenger) was further used to verify the activation of ROS-MAPK pathway by FJHQ. Results We observed that FJHQ induced autophagosomes in NSCLC cells and increased the levels of P62 and LC3-II protein expression in a concentration- and time-gradient-dependent manner, indicating that autophagic flux was inhibited. Co-localization experiments further showed that while FJHQ did not inhibit autophagosome and lysosome fusion, it affected the maturation of cathepsin and thus inhibited the autophagic pathway. Finally, we found that the combination of FJHQ with cisplatin or paclitaxel increased the apoptosis rate of NSCLC cells, due to increased ROS accumulation and further activation of the ROS-MAPK pathway. This synergistic effect could be reversed by NAC. Conclusion Collectively, these results demonstrate that FJHQ is a novel late-stage autophagy inhibitor that can amplify the anti-tumor effect of cisplatin and paclitaxel against NSCLC cells.

Abstract The interplay between genetic alterations and metabolic dysregulation is increasingly recognized as a pivotal axis in cancer pathogenesis. Both elements are mutually reinforcing, thereby expediting the ontogeny and progression of malignant neoplasms. Intriguingly, recent findings have highlighted the translocation of metabolites and metabolic enzymes from the cytoplasm into the nuclear compartment, where they appear to be intimately associated with tumor cell proliferation. Despite these advancements, significant gaps persist in our understanding of their specific roles within the nuclear milieu, their modulatory effects on gene transcription and cellular proliferation, and the intricacies of their coordination with the genomic landscape. In this comprehensive review, we endeavor to elucidate the regulatory landscape of metabolic signaling within the nuclear domain, namely nuclear metabolic signaling involving metabolites and metabolic enzymes. We explore the roles and molecular mechanisms through which metabolic flux and enzymatic activity impact critical nuclear processes, including epigenetic modulation, DNA damage repair, and gene expression regulation. In conclusion, we underscore the paramount significance of nuclear metabolic signaling in cancer biology and enumerate potential therapeutic targets, associated pharmacological interventions, and implications for clinical applications. Importantly, these emergent findings not only augment our conceptual understanding of tumoral metabolism but also herald the potential for innovative therapeutic paradigms targeting the metabolism–genome transcriptional axis.

We prepared AlGaN/GaN high electron mobility transistors (HEMTs) with GaN cap thicknesses of 0, 1, 3, and 5 nm and compared the material characteristics and device performances. It was found that the surface morphology of the epitaxial layer was effectively improved after the introduction of the GaN cap layer. With the increase of the GaN cap thickness, the carrier concentration (ns) decreased and the carrier mobility (μH) increased. Although the drain saturation current (IdSat) of the device decreased with the increasing GaN cap thickness, the excessively thin GaN layer was not suitable for the cap layer. The thicker GaN layer not only improved the surface topography of the epitaxial layer but also effectively improved the off-state characteristics of the device. The optimal cap thickness was determined to be 3 nm. With the introduction of the 3 nm GaN cap, the IdSat was not significantly reduced. However, both the off-state gate leakage current (IgLeak) and the off-state leakage current (IdLeak) decreased by about two orders of magnitude, and the breakdown voltage (BV) increased by about 70 V.

The cultivated soybean (Glycine max (L.) Merrill) is domesticated from wild soybean (Glycine soja) and has heavier seeds with a higher oil content than the wild soybean. In this study, we identified a novel candidate gene associated with SW using a genome-wide association study (GWAS). The candidate gene GmWRI14-like was detected by GWAS analysis in three consecutive years. By constructing transgenic soybeans overexpressing the GmWRI14-like gene and gmwri14-like soybean mutants, we found that overexpression of GmWRI14-like increased the SW and increased total fatty acid content. We then used RNA-seq and qRT-PCR to identify the target genes directly or indirectly regulated by GmWRI14-like. Transgenic soyabeans overexpressing GmWRI14-like showed increased accumulation of GmCYP78A50 and GmCYP78A69 than non-transgenic soybean lines. Interestingly, we also found that GmWRI14-like proteins could interact with GmCYP78A69/GmCYP78A50 using yeast two-hybrid and bimolecular fluorescence complementation. Our results not only shed light on the genetic architecture of cultivated soybean SW, but also lays a theoretical foundation for improving the SW and oil content of soybeans.

BackgroundCryptosporidium infections in humans typically result in symptoms such as abdominal pain and diarrhea. When the diarrhea is severe, it can cause serious complications and even be life-threatening, especially in patients with compromised immune systems.Case presentationHere, we reported the use of metagenomic next-generation sequencing (mNGS) to assist in the diagnosis and treatment of a 10-year-old boy with severe Cryptosporidium infection. Despite the absence of any history of immunocompromise, the infection still resulted in severe symptoms, including shock, as well as damage to his pancreas and kidneys. The mNGS tests detected the presence of Cryptosporidium parvum when conventional methods failed. The patient received anti-parasite treatment along with supportive care to manage the condition. With disease surveillance based on regular clinical tests and sequential mNGS tests, the child recovered from the severe conditions.ConclusionOur study emphasized the importance of recognizing the potential severity of Cryptosporidium infection, even among individuals with normal immune systems. Timely diagnosis and ongoing monitoring are essential for patient prognosis.

The identification of ancient landslides has become a challenging task due to the long-term reconstruction and sediment cover, which obscure the original geomorphic characteristics of these landslides. To address this issue, a comprehensive remote sensing identification model, known as GTVI, is developed using the Object Based Image Analysis (OBIA) based on multi-source and high-resolution remote sensing data in the Dadu River Basin. The study reveals significant differences in texture, hue, shape, and adjacency topology between ancient landslides and reactivated landslides. The gray level co-occurrence matrix entropy (GLCM), terrain roughness index (TRI) and vegetation index (NDVI) effectively capture the information related to ancient landslides. The feasibility of the GTVI (GLCM and Terrain roughness and Vegetation index) model is confirmed through field investigations and remote sensing image analysis of typical landslides, demonstrating its high accuracy. This research provides a valuable method and technical reference for the rapid identification of ancient landslides in plateau canyon areas.

BackgroundLead is widely distributed. Lead exposure interferes with early life development in zebrafish, but the mechanisms by which lead exposure affects skeletal development and cardiac development are not clear as yet. ObjectiveTo investigate the molecular mechanisms of bone development and cardiac development toxicity induced by lead acetate exposure. MethodsZebrafish embryos were exposed to different concentrations of lead acetate (0, 6, 12, 24, and 48 μmol·L−1) for 3 h post-fertilization (3 hpf) until 5 d post-fertilization (5 dpf). The malformation phenotypes of 5 dpf were counted, and the mRNA expressions of spinal development-related genes (bmp2b, bmp4, bmp9, runx2a, runx2b) and heart development-related genes (nkx2.5, myh6, myh7) were detected by quantitative PCR (qPCR). Expressions of genes of development-related regulatory pathways including Wnt/β-catenin pathway (wnt5a, wnt8a, wnt10a, β-catenin) and TGF-β pathway (tgf-β1, tgf-β2) as well as key molecule eph of Eph-Ephrin signaling were analyzed. ResultsAt 5 dpf, the zebrafish in the lead acetate treated groups showed deformed phenotypes including spinal curvature and pericardial sac edema compared to the control group. In the lead acetate groups at 24 and 48 μmol·L−1, the spinal curvature deformity rates reached 26.47% and 71.52% (P

We propose a low loss and high selectivity bandpass filter with defected structure on GaN-on-Silicon. GaN-on-Si exhibits a high insertion loss due to the presence of parasitic channels at the AlN/Si interface. It is necessary to strengthen the coupling between the resonators to achieve a low loss. However, this results in weaker suppression of adjacent channels and lower selectivity of frequencies. The designed filter consists of square spiral defect structure resonators and a step impedance resonator, which provides tunable transmission zero and facilitates the adjustment of pass band. With an interdigitated capacitor, at a frequency span from 3.3 to 4.9 GHz, the proposed filter has a low insertion loss of 2.71dB and improves the suppression of adjacent channel (5.8 GHz) by 11.2 dB compared to the traditional SIR filter. The out-of-band suppression of the filter is better than 15.93 dB at 20 GHz. Compared to the traditional SIR filter, the proposed filter achieves a steep transition zone, and an out-of-band rejection reduction by at least 6.6 dB.

We present a high-performance AlGaN/GaN high electron mobility transistors (HEMTs) on silicon substrate with novel stacked passivation layer (HfO2/SiO2). The stacked passivation structure can effectively modulate the electric field and reduce the electric field peak on the gate side, thus improving the breakdown voltage of the device. The prepared device with a gate length of 450 nm has a unit current gain cutoff frequency (fT) of 31.5 GHz, a maximum oscillation frequency (fMAX) of 46.3 GHz, and a three-terminal OFF-state breakdown voltage (BVgd) of 140 V at the gate-drain distance of $2.3~\mu \text{m}$ . The estimated Johnson’s figure of merit (J-FOM = BVgd $\times \text{f}$ T) is 4.4 THz•V, which is three and five times higher than that of the device with single HfO2 passivation layer and single SiO2 passivation layer, respectively. Furthermore, a significant suppression of the current collapse (~5.7%) is observed due to the electric field redistribution near the drain region. The results show that the AlGaN/GaN HEMTs with stacked passivation layer proved to be a promising candidate for high-performance radio frequency (RF) power device applications.

Abstract Background CRISPR-based toolkits have dramatically increased the ease of genome and epigenome editing. SpCas9 is the most widely used nuclease. However, the difficulty of delivering SpCas9 and inability to modulate its expression in vivo hinder its widespread adoption in large animals. Results Here, to circumvent these obstacles, a doxycycline-inducible SpCas9-expressing (DIC) pig model was generated by precise knock-in of the binary tetracycline-inducible expression elements into the Rosa26 and Hipp11 loci, respectively. With this pig model, in vivo and/or in vitro genome and epigenome editing could be easily realized. On the basis of the DIC system, a convenient Cas9-based conditional knockout strategy was devised through controlling the expression of rtTA component by tissue-specific promoter, which allows the one-step generation of germline-inherited pigs enabling in vivo spatiotemporal control of gene function under simple chemical induction. To validate the feasibility of in vivo gene mutation with DIC pigs, primary and metastatic pancreatic ductal adenocarcinoma was developed by delivering a single AAV6 vector containing TP53-sgRNA, LKB1-sgRNA, and mutant human KRAS gene into the adult pancreases. Conclusions Together, these results suggest that DIC pig resources will provide a powerful tool for conditional in vivo genome and epigenome modification for fundamental and applied research.

Wake-up stroke (WUS) refers to acute cerebrovascular disease without new onset stroke symptoms at bedtime whereas new onset neurological deficits after waking up or during sleep. With unknown onset time of symptoms, most cases are ischemic stroke. Recently, with the exploration of the pathogenesis of WUS and the application and development of imaging techniques such as electron computed tomography and magnetic resonance imaging, it is possible to explore the ischemic penumbra and cerebral perfusion, judge the presence of salvageable brain tissue, and develop a suitable treatment plan, which has become a hot spot in clinical research. This review focuses on the clinical diagnosis and treatment of stroke after waking up.

Significant advances have been achieved in understanding the critical role of enhancer RNAs (eRNAs) in the complex field of gene regulation. However, notable uncertainty remains concerning the biology of eRNAs, highlighting the need for continued research to uncover their exact functions in cellular processes and diseases. We present a comprehensive study to scrutinize mutation density patterns, mutation strand bias, and mutation burden in eRNAs across multiple cancer types. Our findings reveal that eRNAs exhibit mutation strand bias akin to that observed in protein-coding RNAs. We also identified a novel pattern, in which mutation density is notably diminished around the central region of the eRNA, but conspicuously elevated towards both the beginning and end. This pattern can be potentially explained by a mechanism involving heightened transcriptional activity and the activation of transcription-coupled repair. The central regions of the eRNAs appear to be more conserved, hinting at a potential mechanism preserving their structural and functional integrity, while the extremities may be more susceptible to mutations due to increased exposure. The evolutionary trajectory of this mutational pattern suggests a nuanced adaptation in eRNAs, where stability at their core coexists with flexibility at their extremities, potentially facilitating their diverse interactions with other genetic entities.

Objective: The stability of antioxidant peptide activity of safflower seed protein with different molecular weight was studied. Methods: Using shelled safflower seed meal as experimental material, antioxidant peptides were prepared by compound enzymatic hydrolysis. The scavenging ability of 1-diphenyl-2-trinitrophenylhydrazine (DPPH) free radical, superoxide anion radical (O2−·) and hydroxyl radical (·OH) were used as indexes. The effects of environmental factors such as temperature, pH, food raw materials, metal ions and simulated gastrointestinal digestion on the activity of antioxidant peptides from safflower seeds with different molecular weight were studied. Results: The activities of the protease hydrolysates 10 kDa) were significantly lower than those before separation (PZn2+>K+>Mg2+>Ca2+, was stable after simulated gastrointestinal digestion, and the maintenance rate was 80% (P

Abstract Background Heart rate, acidosis, consciousness, oxygenation, and respiratory rate (HACOR) have been used to predict noninvasive ventilation (NIV) failure. However, the HACOR score fails to consider baseline data. Here, we aimed to update the HACOR score to take into account baseline data and test its predictive power for NIV failure primarily after 1–2 h of NIV. Methods A multicenter prospective observational study was performed in 18 hospitals in China and Turkey. Patients who received NIV because of hypoxemic respiratory failure were enrolled. In Chongqing, China, 1451 patients were enrolled in the training cohort. Outside of Chongqing, another 728 patients were enrolled in the external validation cohort. Results Before NIV, the presence of pneumonia, cardiogenic pulmonary edema, pulmonary ARDS, immunosuppression, or septic shock and the SOFA score were strongly associated with NIV failure. These six variables as baseline data were added to the original HACOR score. The AUCs for predicting NIV failure were 0.85 (95% CI 0.84–0.87) and 0.78 (0.75–0.81) tested with the updated HACOR score assessed after 1–2 h of NIV in the training and validation cohorts, respectively. A higher AUC was observed when it was tested with the updated HACOR score compared to the original HACOR score in the training cohort (0.85 vs. 0.80, 0.86 vs. 0.81, and 0.85 vs. 0.82 after 1–2, 12, and 24 h of NIV, respectively; all p values 14 after 1–2 h of NIV, the rate of NIV failure was 12.4%, 38.2%, 67.1%, and 83.7%, respectively. Conclusions The updated HACOR score has high predictive power for NIV failure in patients with hypoxemic respiratory failure. It can be used to help in decision-making when NIV is used.

Abstract The cochlea consists of multiple types of cells, including hair cells, supporting cells and spiral ganglion neurons, and is responsible for converting mechanical forces into electric signals that enable hearing. Genetic and environmental factors can result in dysfunctions of cochlear and auditory systems. In recent years, gene therapy has emerged as a promising treatment in animal deafness models. One major challenge of the gene therapy for deafness is to effectively deliver genes to specific cells of cochleae. Here, we screened and identified an AAV-ie mutant, AAV-ie-K558R, that transduces hair cells and supporting cells in the cochleae of neonatal mice with high efficiency. AAV-ie-K558R is a safe vector with no obvious deficits in the hearing system. We found that AAV-ie-K558R can partially restore the hearing loss in Prestin KO mice and, importantly, deliver Atoh1 into cochlear supporting cells to generate hair cell-like cells. Our results demonstrate the clinical potential of AAV-ie-K558R for treating the hearing loss caused by hair cell death.

The geotechnical engineering field and indoor parameter test data are the foundation of engineering construction, design and evaluation. The existence of abnormal data often misleads the determination of parameters such as construction and design. Data anomaly detection is the most basic but extremely important task to ensure the safety and reliability of a project. Aiming at the blindness of detection due to the lack of model selection in traditional anomaly detection algorithms, this paper proposes an anomaly detection model system based on a combination of meta-learning outlier detection (MetaOD) and data mining algorithms. The system first selects the initial model class and its parameters suitable for different data types according to the characteristics of the data, averages the selected parameters of the same type of algorithm, and then uses the selected algorithm to diagnose data anomalies, thereby improving the anomaly accuracy of detection. To evaluate the effectiveness of the model, the machine learning test dataset (glass dataset) proposed by the University of California Irvine, is used for test analysis. The results show that the accuracy rate of anomaly detection using this model system reaches 96.41%, which is much higher than that of other detection algorithms. Finally, the model system is applied to the uniaxial compressive strength dataset of the Macau granite and the groundwater monitoring data of the Junchang Tunnel to carry out anomaly detection and analysis and to identify 9 and 10 abnormal points, respectively.

Abstract Background Despite extensive investigations on photothermal therapy, the clinical application is restricted due to poor stability, low therapeutic efficacy of photothermal therapy agents and its affinity loss in the multistep synthesis of delivery carriers. To address this, we designed an IR792-MCN@ZIF-8-PD-L1 siRNA (IM@ZP) nanoparticle drug delivery system. IM@ZP was prepared by in situ synthesis and physical adsorption, followed by characterization. Photothermal conversion ability of IM@ZP was assessed by irradiation of near-infrared (NIR) laser, followed by analysis of its effect on 4T1 cell viability, maturation of dendritic cells (DCs) and the secretion of related cytokines in vitro, and the changes of tumor infiltrating T cells and natural killer (NK) cells in vivo. Subcutaneous 4T1 tumor-bearing mouse and lung metastasis models were established to investigate the role of IM@ZP in killing tumor and inhibiting metastasis in vivo. Results IM@ZP was uniform nanoparticles of 81.67 nm with the characteristic UV absorption peak of IR792, and could effectively adsorb PD-L1 siRNA. Under the irradiation of 808 nm laser, IM@ZP exhibited excellent photothermal performance. IM@ZP could be efficiently uptaken by 4T1 cells, and had high transfection efficiency of PD-L1 siRNA. Upon NIR laser irradiation, IM@ZP effectively killed 4T1 cells, upregulated HSP70 expression, induced DC maturation and increased secretion of TNF-α and IL-6 in vitro. Moreover, in vivo experimental results revealed that IM@ZP enhanced photothermal immunotherapy as shown by promoted tumor infiltrating CD8 + and CD4 + T cells and NK cells, and inhibited tumor growth and lung metastasis. Conclusion Together, biocompatible IM@ZP nanoparticles result in high photothermal immunotherapy efficiency and may have a great potential as a delivery system for sustained cancer therapy. Graphical Abstract

In recent years, numerous ancient landslides initially triggered by historic earthquakes on the eastern Tibetan Plateau have been reactivated by fault activity and heavy rainfall, causing severe human and economic losses. Previous studies have indicated that short-term heavy rainfall plays a crucial role in the reactivation of ancient landslides. However, the deformation behavior and reactivation mechanisms of seasonal rainfall-induced ancient landslides remain poorly understood. In this paper, taking the Dandu ancient landslide as an example, field investigations, ring shear experiments, and interferometric synthetic aperture radar (InSAR) deformation monitoring were performed. The cracks in the landslide, formed by fault creeping and seismic activity, provide pathways for rainwater infiltration, ultimately reducing the shear resistance of the slip zone and causing reactivation and deformation of the Dandu landslide. The deformation behavior of landslides is very responsive to seasonal rainfall, with sliding movements beginning to accelerate sharply during the rainy season and decelerating during the dry season. However, this response generally lags by several weeks, indicating that rainfall takes time to infiltrate into the slip zone. These research results could help us better understand the reactivation mechanism of ancient landslides triggered by seasonal rainfall. Furthermore, these findings explain why many slope failures take place in the dry season, which typically occurs approximately a month after the rainy season, rather than in the rainy season itself.

Black silicon properties are investigated in the wavelength range extending from 0.2 to 25 μm with a focus on the mid‐infrared (MIR). It is demonstrated that concurrently increasing the initial level of doping of bare silicon, with given limits, enables reaching even higher absorptance and higher spectral range. Unprecedented light absorptance levels are obtained on black silicon with up to 99.5% in the spectral range from 1 to 8 μm and above 90% until 20 μm, leading to ultrabroadband, ultrablack silicon surfaces. The synergetic effects of morphology and volume doping are elucidated; in particular, how the high aspect‐ratio of conical nanostructures plays a crucial role. The experimental findings are analyzed with numerical simulations involving plasmonic effects of highly doped silicon and supported by tomographic processing of microscopy images. Guidelines and corresponding manufacturing routes are provided by which ultrabroadband, ultrablack silicon surfaces can be obtained within minutes of plasma processing, with no need for further functionalization. With the scalable manufacturing involving solely pure silicon, the resulting ultrabroadband perfect absorbers should be of benefit for large‐scale deployment of radiative cooling devices, blackbody infrared light sources, and infrared radiation sensing.

Grifola frondosa is an edible medicinal mushroom that has been proven to have a variety of health benefits. The main active ingredients of this mushroom are polysaccharides. In this study, ultrasonic-assisted extraction was used to obtain crude Grifola frondosa polysaccharides (GFPs). Then, purified GFP was obtained after purification. The optimum extraction conditions were an extraction time of 71 min, an extraction temperature of 90°C in a solid-to-liquid ratio of 1:37 g/mL, and an ultrasonic power of 500 W. GFP was purified using DEAE-52 and Sephadex G-100. The structural characterization of GFP was performed using Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), ion chromatography (IC), and ultraviolet (UV) visible photometry. The morphology of GFP was analyzed by scanning electron microscopy (SEM), thermogravimetric differential scanning calorimetry (TG-DSC), and Congo red testing. In addition, the administration of GFP in oxazolone (OXZ)-induced ulcerative colitis (UC) in mice was found to prevent weight loss. Different doses of GFP (80, 160, and 320 mg/kg body weight) were used, and sulfapyridine (SASP) was used as a positive control (370 mg/kg body weight) for the treatment of OXZ-induced UC. After treatment, the mice were killed, and blood and colon tissue samples were collected. GFP was found to prevent decreases in colon length and the levels of leukocytes, platelets, and neutrophils in UC mice. Moreover, GFP also decreased the expression of pro-inflammatory cytokines [tumor necrosis factor (TNF)-α and interleukin (IL)-1 β], increased IL-10, and reduced colon injury in UC mice. The results showed that Under these conditions, the predicted polysaccharide yield was 21.72%, and the actual extraction rate was 21.13%. The polysaccharide composition (molar ratio) was composed of fucose (0.025), glucosamine hydrochloride (0.004), galactose (0.063), glucose (0.869), and mannose (0.038). GFP was also found to have a typical absorption peak, and the GFP extracted using the ultrasound-assisted extraction protocol was mainly β-glucan. These results indicate that ultrasound-assisted extraction of GFP could reduce OXZ-induced intestinal inflammation as a promising candidate for the treatment of UC, with the potential for development as a food supplement to improve intestinal diseases.

IntroductionIt has been reported that GRB7 is closely related to a variety of human solid tumors, but its role in gastric cancer has not been reported yet. The purpose of this study was to investigate the expression level and intracellular effects of GRB7 in human gastric cancer.MethodsReal-time fluorescent quantitative PCR and Western blot were used to detect the expression of GRB7 in gastric cancer cell lines. The immunohistochemical staining and SPSS analysis verified the GRB7 protein expression. Stable gastric cancer cell lines, MTT experiments, clone formation experiments, cell cycle flow cytometry experiments, sphere formation experiments and lateral subpopulation cell sorting experiments were conducted to investigate the role of GRB7 in gastric cancer cells.ResultsWe found that the expression of GRB7 in gastric cancer cell lines was higher than that of the corresponding normal gastric epithelial cells, and correspondingly higher in gastric cancer tissues than its paired adjacent tissues. GRB7 protein was expressed more highly in cancer tissues than in adjacent tissues. GRB7 protein expression levels were positively correlated with the clinical stage of gastric cancer patients, and negatively correlated with the survival prognosis of patients. GSEA analysis of GRB7 mRNA levels in gastric cancer tissues and normal gastric epithelial tissues from public databases showed that GRB7 may affect cell proliferation and related processes of intracellular stem cells. GRB7 can promote the proliferation of gastric cancer cells and is positively related to the self-renewal ability of gastric cancer stem cells.DiscussionThis study shows that GRB7 molecules highly expressed in gastric cancer tissues can promote the proliferation of gastric cancer cells and increase the proportion of gastric cancer stem cells, so it is expected to become a diagnostic molecule or potential therapeutic target for gastric cancer.

RNA-binding proteins (RBPs) are a set of proteins involved in many steps of post-transcriptional regulation to maintain cellular homeostasis. Ovarian cancer (OC) is the most deadly gynecological cancer, but the roles of RBPs in OC are not fully understood. Here, we reported that the RBP QKI5 was significantly negatively correlated with aggressive tumor stage and worse prognosis in serous OC patients. QKI5 could suppress the growth and metastasis of OC cells both in vitro and in vivo. Transcriptome analysis showed that QKI5 negatively regulated the expression of the transcriptional coactivator TAZ and its downstream targets (e.g., CTGF and CYR61). Mechanistically, QKI5 bound to TAZ mRNA and recruited EDC4, thus decreasing the stability of TAZ mRNA. Functionally, TAZ was involved in the QKI5-mediated tumor suppression of OC cells, and QKI5 expression was inversely correlated with TAZ, CTGF, and CYR61 expression in OC patients. Together, our study indicates that QKI5 plays a tumor-suppressive role and negatively regulates TAZ expression in OC.

ABSTRACT Alginate (ALG) is known to alleviate intestinal inflammation in inflammatory bowel disease, but its mechanism of action remains elusive. In the present study, we studied the involvement of the intestinal microbiota and bile acid (BA) metabolism in ALG-mediated anti-inflammatory effects in mice. A combination of 16S rRNA gene amplicon sequencing, shotgun metagenomic sequencing, and targeted BA metabolomic profiling was employed to investigate structural and functional differences in the colonic microbiota and BA metabolism in dextran sulfate sodium (DSS)-treated mice with or without dietary supplementation of ALG. We further explored the role of the intestinal microbiota as well as a selected ALG-enriched bacterium and BA in DSS-induced colitis. Dietary ALG alleviated DSS-mediated intestinal inflammation and enriched a small set of bacteria including Bifidobacterium animalis in the colon (P

Abstract Background Chronic kidney disease (CKD) is a common health challenge. There are some risk models predicting CKD adverse outcomes, but seldom focus on the Mongoloid population in East Asian. So, we developed a simple but intuitive nomogram model to predict 3-year CKD adverse outcomes for East Asian patients with CKD. Methods The development and internal validation of prediction models used data from the CKD-ROUTE study in Japan, while the external validation set used data collected at the First People’s Hospital of Foshan in southern China from January 2013 to December 2018. Models were developed using the cox proportional hazards model and nomogram with SPSS and R software. Finally, the model discrimination, calibration and clinical value were tested by R software. Results The development and internal validation data-sets included 797 patients (191 with progression [23.96%]) and 341 patients (89 with progression [26.10%]), respectively, while 297 patients (108 with progression [36.36%]) were included in the external validation data set. The nomogram model was developed with age, eGFR, haemoglobin, blood albumin and dipstick proteinuria to predict three-year adverse-outcome-free probability. The C-statistics of this nomogram were 0.90(95% CI, 0.89–0.92) for the development data set, 0.91(95% CI, 0.89–0.94) for the internal validation data set and 0.83(95% CI, 0.78–0.88) for the external validation data-set. The calibration and decision curve analyses were good in this model. Conclusion This visualized predictive nomogram model could accurately predict CKD three-year adverse outcomes for East Asian patients with CKD, providing an easy-to-use and widely applicable tool for clinical practitioners.

Digital rural development has become an emerging dynamic force for high-quality rural development in China. This paper constructs the “environmental-economic-social” analysis framework for digital rural development, analyzes the spatial variation of the digital rural development level (DRDL) in Chinese counties in 2020, and conducts the factor detection and interaction detection of its influencing factors. It is found that: (1) digital rural development has its own unique spatial differentiation mechanism, which can be analyzed from three dimensions: environmental system, economic system, and social system, which play a fundamental role, decisive role, and a magnifying effect on digital rural development, respectively. (2) The DRDL in China’s counties has significant spatial distribution, spatial correlation, and spatial clustering characteristics. The DRDL in general shows a decreasing distribution trend from coastal to inland regions, and the overall differences in DRDL mainly come from intra-regional differences rather than inter-regional differences. The rural infrastructure digitalization dimension has stronger spatial correlation while the spatial correlation of the rural governance digitalization dimension is weaker. There are obvious hotspot and coldspot areas in the DRDL, with large differences between the coldspot and hotspot areas of different sub-dimensions. (3) The spatial divergence of the DRDL is closely related to geographical elements and is the result of the combined effect of several geographical factors. The factor detection results show that the dominant factors within the four regions are significant different. The interaction detection results show that the driving force of the two-factor interaction is stronger than that of the single-factor interaction and that the interaction among the factors further deepens the spatial differentiation of the DRDL.