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This article explores the criteria for fixed‐time stability (FxTS) within nonlinear impulsive dynamical systems, encompassing both stabilizing and destabilizing impulses. Initially, employing the Lyapunov method, the article delineates a criterion for FxTS, particularly when impulsive sequences are delineated by an average impulsive interval. Following this, the article innovatively applies two integral inequalities to introduce an optimized criterion for uniform impulsive sequences, evidencing its lesser conservativeness relative to the initial criterion. Moreover, this article derives a necessary condition for dynamical systems subjected to destabilizing impulses. Intriguingly, the investigation reveals the existence of a minimal threshold for the maximum impulsive interval, below which the system cannot achieve FxTS. This result elucidates why existing literature uniformly imposes a specific condition on the impulsive interval for destabilizing impulses. Finally, the efficacy of the proposed theory is underscored through numerical examples. [ABSTRACT FROM AUTHOR]

Tyrosine kinase inhibitors have been the standard treatment for patients with Philadelphia chromosome-positive (Ph+) leukemia. However, a series of issues, including drug resistance, relapse and intolerance, are still an unmet medical need. Here, we report the targeted siRNA-based lipid nanoparticles in Ph+ leukemic cell lines for gene therapy of Ph+ leukemia, which specifically targets a recently identified NEDD8 E3 ligase RAPSYN in Ph+ leukemic cells to disrupt the neddylation of oncogenic BCR-ABL. To achieve the specificity for Ph+ leukemia therapy, a single-chain fragment variable region (scFv) of anti-CD79B monoclonal antibody was covalently conjugated on the surface of OA2-siRAPSYN lipid nanoparticles to generate the targeted lipid nanoparticles (scFv-OA2-siRAPSYN). Through effectively silencing RAPSYN gene in leukemic cell lines by the nanoparticles, BCR-ABL was remarkably degraded accompanied by the inhibition of proliferation and the promotion of apoptosis. The specific targeting, therapeutic effects and systemic safety were further evaluated and demonstrated in cell line-derived mouse models. The present study has not only addressed the clinical need of Ph+ leukemia, but also enabled gene therapy against a less druggable target. [ABSTRACT FROM AUTHOR]

Clear cell renal carcinoma (ccRCC), the most common subtype of renal cell carcinoma, has the high heterogeneity of a highly complex tumor microenvironment. Existing clinical intervention strategies, such as target therapy and immunotherapy, have failed to achieve good therapeutic effects. In this article, single-cell transcriptome sequencing (scRNA-seq) data from six patients downloaded from the GEO database were adopted to describe the tumor microenvironment (TME) of ccRCC, including its T cells, tumor-associated macrophages (TAMs), endothelial cells (ECs), and cancer-associated fibroblasts (CAFs). Based on the differential typing of the TME, we identified tumor cell-specific regulatory programs that are mediated by three key transcription factors (TFs), whilst the TF EPAS1/HIF-2 α was identified via drug virtual screening through our analysis of ccRCC's protein structure. Then, a combined deep graph neural network and machine learning algorithm were used to select anti-ccRCC compounds from bioactive compound libraries, including the FDA-approved drug library, natural product library, and human endogenous metabolite compound library. Finally, five compounds were obtained, including two FDA-approved drugs (flufenamic acid and fludarabine), one endogenous metabolite, one immunology/inflammation-related compound, and one inhibitor of DNA methyltransferase (N4-methylcytidine, a cytosine nucleoside analogue that, like zebularine, has the mechanism of inhibiting DNA methyltransferase). Based on the tumor microenvironment characteristics of ccRCC, five ccRCC-specific compounds were identified, which would give direction of the clinical treatment for ccRCC patients. [ABSTRACT FROM AUTHOR]

This paper examines fixed-time synchronization (FxTS) for two-dimensional coupled reaction–diffusion complex networks (CRDCNs) with impulses and delay. Utilizing the Lyapunov method, a FxTS criterion is established for impulsive delayed CRDCNs. Herein, impulses encompass both synchronizing and desynchronizing variants. Subsequently, by employing a Lyapunov–Krasovskii functional, two FxTS boundary controllers are formulated for CRDCNs with Neumann and mixed boundary condition, respectively. It is observed that vanishing Dirichlet boundary contributes to the synchronization of the CRDCNs. Furthermore, this study calculates the optimal constant for the Poincaré inequality in the square domain, which is instrumental in analyzing FxTS conditions for boundary controllers. Conclusive numerical examples underscore the efficacy of the proposed theoretical findings. [ABSTRACT FROM AUTHOR]

When a problem has more than one solution, it is often important, depending on the underlying context, to enumerate (i.e., to list) them all. Even when the enumeration can be done in polynomial delay, that is, spending no more than polynomial time to go from one solution to the next, this can be costly as the number of solutions themselves may be huge, including sometimes exponential. Furthermore, depending on the application, many of these solutions can be considered equivalent. The problem of an efficient enumeration of the equivalence classes or of one representative per class (without generating all the solutions), although identified as a need in many areas, has been addressed only for very few specific cases. In this paper, we provide a general framework that solves this problem in polynomial delay for a wide variety of optimization problems solvable by dynamic programming algorithms, and for certain types of equivalence relations between solutions. [ABSTRACT FROM AUTHOR]

Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are equally recommended as first-line treatments for antiviral treatment-naïve (ART-naïve) chronic hepatitis B (CHB) patients by practice guidelines because of their similarly high antiviral efficacy and low resistance rate. However, whether one is superior to the other in terms of hepatocellular carcinoma (HCC) prevention is currently largely controversial. We aimed to identify and synthesize these existing studies regarding the HCC risk of these two highly potent antivirals in treatment-naïve CHB patients. PubMed, EMBASE, and Cochrane Library were searched for studies between January 1, 2012 and June 25, 2022. These studies used ETV monotherapy and/or TDF monotherapy to treat ART-naïve CHB patients and reported the incidence of HCC. The extracted data were analyzed using a DerSimonian–Laird random-effects models. The HCC incidence difference was expressed as hazard ratio (HR) and 95% confidence interval (95% CI). A total of 17 studies with 90,897 ART-naïve CHB patients (ETV = 60,980 vs TDF = 29,917) were included in this meta-analysis. Compared with ETV, TDF was associated with a significant lower cumulative incidence of HCC (HR 0.66; 95% CI 0.56–0.76). No significant heterogeneity or publication bias was found among the included studies (I2 = 48.1%, Begg's p = 0.363 and Egger's p = 0.748). TDF is associated with a lower risk of HCC compared with entecavir in ART-naïve CHB patients. The results suggest that TDF may be a better option for ART-naïve CHB patients with high HCC risks. [ABSTRACT FROM AUTHOR]

Identifying urban employment centers (UECs) is crucial for understanding urban spatial structures. Conventional identification methods use census-type aggregated data. The increasing pervasiveness of mobile phone data provides new possibilities to analyze UECs at finer spatial resolution but requires novel identification methods. This study proposes a new approach, the Locally Decaying Model (LDM), to fit the employment density locally and identify UECs based on statistically significant local peaks. We compared the proposed LDM with conventional methods by Monte-Carlo simulation and real data experiments on employment distributions generated from Shanghai mobile phone data. The Monte-Carlo simulation showed that the LDM performed significantly better. The Shanghai case study demonstrated greater stability of the LDM in identifying UEC numbers and locations on aggregated data than the conventional methods. Furthermore, UECs extracted by LDM from the employment density raster were more consistent with the existing local plan. This research contributed a new subcenter identification method that can be applied to recently available urban big data and a comprehensive analytical framework for evaluating such methods. [ABSTRACT FROM AUTHOR]

HIV and HBV infection are both serious public health challenges. There are more than approximately 4 million patients coinfected with HIV and HBV worldwide, and approximately 5% to 15% of those infected with HIV are coinfected with HBV. Disease progression is more rapid in patients with coinfection, which significantly increases the likelihood of patients progressing from chronic hepatitis to cirrhosis, end-stage liver disease, and hepatocellular carcinoma. HIV treatment is complicated by drug interactions, antiretroviral (ARV) hepatotoxicity, and HBV-related immune reconditioning and inflammatory syndromes. Drug development is a highly costly and time-consuming procedure with traditional experimental methods. With the development of computer-aided drug design techniques, both machine learning and deep learning have been successfully used to facilitate rapid innovations in the virtual screening of candidate drugs. In this study, we proposed a graph neural network-based molecular feature extraction model by integrating one optimal supervised learner to replace the output layer of the GNN to accurately predict the potential multitargets of HIV-1/HBV coinfections. The experimental results strongly suggested that DMPNN + GBDT may greatly improve the accuracy of binary-target predictions and efficiently identify the potential multiple targets of HIV-1 and HBV simultaneously. [ABSTRACT FROM AUTHOR]

Pathway genes functionally participate in the same biological process. They typically act cooperatively, and none is considered dispensable. The dominant paradigm in drug discovery is the one-to-one strategy, which aims to find the most sensitive drug to act on an individual target. However, many complex diseases, such as cancer, are caused by dysfunction among multiple-gene pathways, not just one. Therefore, identifying pathway genes that are responsive to synthetic compounds in a global physiological environment may be more effective in drug discovery. The high redundancy of crosstalk between biological pathways, though, hints that the covariance matrix, which only connects genes with strong marginal correlations, may miss higher-level interactions, such as group interactions. We herein report the development of DPADM—a Drug-Pathway association Detection Model that infers pathways responsive to specific drugs. This model elucidates higher-level gene–gene interactions by evaluating the conditional dependencies between genes under different drug treatments. The advantage of the proposed method is demonstrated using simulation studies by comparing with another two methods. We applied this model to the Connectivity Map data set (CMap), and demonstrated that DPADM is able to identify many drug-pathway associations, such as mitoxantrone (MTX)- PI3K/AKT association, which targets the topological conditions of DNA transcription. Surprisingly, apart from identifying pathways corresponding to specific drugs, our methodology also revealed new drug-related pathways with functions similarly to those of seed genes. [ABSTRACT FROM AUTHOR]

Epigenetics, referring to genetic modifications that change gene expression, but which are not encoded in DNA, has been shown to be related to oncology, with the potential to influence associated treatments. As such, epigenetic drugs comprise an important new field in cancer therapy; however, drug development is a high-cost and time-consuming procedure. Different epigenetic modifications, such as mutations in DNA methyltransferase and somatic mutations in core histone genes that lead to a global loss of the histone modifications, have innumerable relationships. In this article, we propose a graph neural network-based model for the extraction of molecular features, thus reducing the computational requirements. Through integration with a popular and efficient supervised learner, our model achieves higher prediction accuracy in both single- and multi-target tasks and can determine the pleiotropy associated with drugs, providing theoretical support for drug combination and discovery research. [ABSTRACT FROM AUTHOR]

Background: Cophylogeny reconciliation is a powerful method for analyzing host-parasite (or host-symbiont) co-evolution. It models co-evolution as an optimization problem where the set of all optimal solutions may represent different biological scenarios which thus need to be analyzed separately. Despite the significant research done in the area, few approaches have addressed the problem of helping the biologist deal with the often huge space of optimal solutions. Results: In this paper, we propose a new approach to tackle this problem. We introduce three different criteria under which two solutions may be considered biologically equivalent, and then we propose polynomial-delay algorithms that enumerate only one representative per equivalence class (without listing all the solutions). Conclusions: Our results are of both theoretical and practical importance. Indeed, as shown by the experiments, we are able to significantly reduce the space of optimal solutions while still maintaining important biological information about the whole space. [ABSTRACT FROM AUTHOR]

Protein modification with small ubiquitin-like modifiers (SUMOs) plays dual roles in prostate cancer (PCa) tumorigenesis and development. Any intermediary of the SUMO conjugation cycle going awry may forfeit the balance between tumorigenic potential and anticancer effects. Deregulated SUMOylation on the androgen receptor and oncoproteins also takes part in this pathological process, as exemplified by STAT3/NF-κB and tumor suppressors such as PTEN and p53. Here, we outline recent developments and discoveries of SUMOylation in PCa and present an overview of its multiple roles in PCa tumorigenesis/promotion and suppression, while elucidating its potential as a therapeutic target for PCa. • The dual opposing roles of SUMOylation in prostate cancer (PCa). • The aberrant expression of SUMO machinery components and deregulation of related signaling pathways occurs in PCa. • Altered SUMOylation of oncoproteins is involved in the initiation and progression as well as inhibition of PCa. • SUMOylation of tumor suppressors including p53 and PTEN regulates tumorigenesis and development of PCa. • SUMOylation is an emerging target for therapeutic interventions of PCa. [ABSTRACT FROM AUTHOR]

Protein modification with small ubiquitin-like modifiers (SUMOs) plays dual roles in prostate cancer (PCa) tumorigenesis and development. Any intermediary of the SUMO conjugation cycle going awry may forfeit the balance between tumorigenic potential and anticancer effects. Deregulated SUMOylation on the androgen receptor and oncoproteins also takes part in this pathological process, as exemplified by STAT3/NF-κB and tumor suppressors such as PTEN and p53. Here, we outline recent developments and discoveries of SUMOylation in PCa and present an overview of its multiple roles in PCa tumorigenesis/promotion and suppression, while elucidating its potential as a therapeutic target for PCa. [ABSTRACT FROM AUTHOR]

Background: Experimental autoimmune encephalomyelitis (EAE) is a model for inflammatory demyelinating diseases of the central nervous system (CNS), a group of autoimmune diseases characterized by inflammatory infiltration, demyelination, and axonal damage. miR-20a is dysregulated in patients with CNS inflammatory demyelinating diseases; however, the function of miR-20a remains unclear. In this study, we intended to explore the role of miR-20a in EAE.Methods: The expression of miR-20a was detected by quantitative real-time PCR (qRT-PCR) in EAE mice and patients with MOG antibody-associated demyelinating diseases. CD4+ T cells of EAE mice were sorted, stimulated, and polarized with miR-20a knockdown. Activation and differentiation of CD4+ T cells were analyzed by flow cytometry. The expression of target gene Map3k9 was detected by qRT-PCR and western blot experiments. The binding of miR-20a to the 3' UTR of Map3k9 was tested by luciferase assays. The feasibility of miR-20a as a therapeutic target to alleviate the severity of EAE was explored by intravenous administration of miR-20a antagomirs to EAE mice.Results: miR-20a was upregulated in splenocytes and lymph node cells, CD4+ T cells, and spinal cords of EAE mice. Moreover, miR-20a knockdown did not influence the activation of antigen-specific CD4+ T cells but promoted their differentiation into Treg cells. Map3k9 was predicted to be a target gene of miR-20a. The expressions of Map3k9 and miR-20a were negatively correlated, and miR-20a knockdown increased the expression of Map3k9. In addition, miR-20a binded to the 3' UTR of Map3k9, and simultaneous knockdown of miR-20a and Map3k9 counteracted the enhanced differentiation of Tregs observed when miR-20a was knocked down alone. Furthermore, injection of miR-20a antagomirs to EAE mice reduced the severity of the disease and increased the proportion of Treg cells in peripheral immune organs.Conclusions: miR-20a suppresses the differentiation of antigen-specific CD4+ T cells into Tregs in EAE by decreasing the expression of Map3k9. miR-20a antagomirs alleviate EAE, suggesting a new therapy for EAE and CNS inflammatory demyelinating diseases. [ABSTRACT FROM AUTHOR]

Advanced single-cell profiling technologies promote exploration of cell heterogeneity, and clustering of single-cell RNA (scRNA-seq) data enables discovery of coexpression genes and network relationships between genes. In particular, single-cell profiling of circulating tumor cells (CTCs) can provide unique insights into tumor heterogeneity (including in triple-negative breast cancer (TNBC)), while scRNA-seq leads to better understanding of subclonal architecture and biological function. Despite numerous reports suggesting a direct correlation between circulating tumor cells (CTCs) and poor clinical outcomes, few studies have provided a thorough heterogeneity characterization of CTCs. In addition, TNBC is a disease with not only intertumor but also intratumor heterogeneity and represents various biological distinct subgroups that may have relationships with immune functions that are not clearly established yet. In this article, we introduce a new scheme for detecting genotypic characterization of single-cell heterogeneities and apply it to CTC and TNBC single-cell RNA-seq data. First, we use an existing mixture exponential family graph model to partition the cell-cell network; then, with the Markov random field model, we obtain more flexible network rewiring. Finally, we find the cell heterogeneity and network relationships according to different high coexpression gene modules in different cell subsets. Our results demonstrate that this scheme provides a reasonable and effective way to model different cell clusters and different biological enrichment gene clusters. Thus, using different internal coexpression genes of different cell clusters, we can infer the differences in tumor composition and diversity. [ABSTRACT FROM AUTHOR]

The Notch signalling pathway in the mammalian ovary regulates granulosa cell proliferation. However, the effects of Notch signalling on steroidogenesis are unclear. In this study we cultured mouse ovarian granulosa cells from preantral follicles in vitro and observed the effect of Notch signalling on steroidogenesis through overexpression, knockdown and inhibition of Notch signalling. Activation of Notch signalling decreased progesterone and oestrogen secretion. In contrast, inhibition of Notch signalling increased the production of progesterone and oestrogen. Expression of the genes for steroidogenic-related enzymes, including 3β-hydroxysteroid dehydrogenase, p450 cholesterol side-chain cleavage enzyme and aromatase, was repressed after stimulation of Notch signalling. The expression of upstream transcription factors, including steroidogenic factor 1 (SF1), Wilms' tumour 1 (Wt1), GATA-binding protein 4 (Gata4) and Gata6, was also inhibited after stimulation of Notch signalling. Production of interleukin (IL)-6 was positively correlated with Notch signalling and negatively correlated with the expression of these transcription factors and enzymes. In conclusion, Notch signalling regulated progesterone and oestrogen secretion by affecting the expression of upstream transcription factors SF1, Wt1, Gata4 and Gata6, as well as downstream steroidogenic-related enzymes. IL-6, which may be regulated directly by Notch signalling, may contribute to this process. Our findings add to the understanding of the diverse functions of Notch signalling in the mammalian ovary. Steroid hormone synthesis is one function of granulosa cells and plays an important role in the maturation and function of reproductive organs. In this study we found that Notch signalling affected progesterone and oestradiol secretion by granulosa cells via regulation of interleukin-6 expression. This finding adds to our understanding of the diverse functions of Notch signalling in the mammalian ovary. [ABSTRACT FROM AUTHOR]

We reported a phenomenon and mechanism of recrystallization evolution in solder joint under thermo-mechanical stress. Ball Grid Array samples fabricated by Sn3.0Ag0.5Cu solder were placed into the thermal cycling test chamber with a temperature range of −55 °C to 125 °C. Characterized using electron backscattered diffraction technique, three stages of recrystallization occurring in the solder joint were found to co-exist in one joint after 2500 thermal cycles. To better understand the formation of recrystallized grains during thermal cycling, especially dislocation substructures at the early stage, thin foils corresponding to different stages of the recrystallization were extracted by focus ion beam from the solder joint and analyzed by high-resolution transmission electron microscope. We summarize the recrystallization process including the annihilation of dislocation dipoles contributes to the evolution of sub-grain boundaries, and then the recrystallized grains are generated by sub-grain rotation mechanism. In addition, the recrystallized grains proceed to the subsequent same cycle until the failure of solder joint. The study provides the theoretical basis and technical support for further improving the thermo-mechanical reliability of Sn-based lead-free solder joints. • Three stages of recrystallization were found to co-exist in one solder joint after 2500 thermal cycles. • The early stage of recrystallization in solder joint was proposed to explain the formation of sub-grains. • The recrystallized grains proceed to the subsequent same cycle until the failure of solder joint. [ABSTRACT FROM AUTHOR]

Motivation Phylogenetic tree reconciliation is the method of choice in analyzing host-symbiont systems. Despite the many reconciliation tools that have been proposed in the literature, two main issues remain unresolved: (i) listing suboptimal solutions (i.e. whose score is 'close' to the optimal ones) and (ii) listing only solutions that are biologically different 'enough'. The first issue arises because the optimal solutions are not always the ones biologically most significant; providing many suboptimal solutions as alternatives for the optimal ones is thus very useful. The second one is related to the difficulty to analyze an often huge number of optimal solutions. In this article, we propose Capybara that addresses both of these problems in an efficient way. Furthermore, it includes a tool for visualizing the solutions that significantly helps the user in the process of analyzing the results. Availability and implementation The source code, documentation and binaries for all platforms are freely available at https://capybara-doc.readthedocs.io/. Contact yishu.wang@univ-lyon1.fr or blerina.sinaimeri@inria.fr Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

In this study, simple shear tests on breakable polydisperse granular materials were simulated using two-dimensional discrete element method (DEM). A new technique of generating polydisperse DEM samples with a smooth and continuous particle size distribution curve was proposed. A modified breakage criterion was introduced to reflect the contact force anisotropy of particles in the numerical sample. The simulation results showed that during the simple shearing, grain crushing in the sample mainly occurred in the contraction process and decreased gradually when the sample began to dilate. As the shearing proceeded to a larger strain, the grain crushing tended to a stable value. This grain crushing trend was in accordance with the evolution of the average normal contact forces of particles in the sample during shearing. The average normal contact forces of potential breakage particles increased in the contraction process and decreased in the dilatancy process. A decrease in the average normal contact forces of potential breakage particles resulted in the decrease in grain crushing during the later stage of shearing. [ABSTRACT FROM AUTHOR]

A novel composite consisting of poly[iron (II) tetraphenylporphyrin] (PFeTPP) and poly(sodium- p -styrenesulfonate) (PSS) modified graphene (Gr), denoted as PFeTPP/PSS-Gr, was obtained by a solvothermal method and used for the voltammetric determination of dopamine (DA). Compared with either pristine PFeTPP or PSS-Gr, the fabricated composite exhibits superior electrocatalytic activity towards the oxidation of DA. Its oxidation peak current shows a linear dependence over the DA concentration in the range from 0.1 to 40 μM, with a detection limit of 5.73 nM ( S / N = 3). Furthermore, the fabricated PFeTPP/PSS-Gr composite can detect DA in the presence of a large excess of ascorbic acid (AA) and uric acid (UA). Our proposed sensor conceivably represents a promising material for bioanalytical applications. [ABSTRACT FROM AUTHOR]

Abstract: Background: Epistatic Miniarray Profiles (EMAP) enable the research of genetic interaction as an important method to construct large-scale genetic interaction networks. However, a high proportion of missing values frequently poses problems in EMAP data analysis since such missing values hinder downstream analysis. While some imputation approaches have been available to EMAP data, we adopted an improved SVD modeling procedure to impute the missing values in EMAP data which has resulted in a higher accuracy rate compared with existing methods. Results: The improved SVD imputation method adopts an effective soft-threshold to the SVD approach which has been shown to be the best model to impute genetic interaction data when compared with a number of advanced imputation methods. Imputation methods also improve the clustering results of EMAP datasets. Thus, after applying our imputation method on the EMAP dataset, more meaningful modules, known pathways and protein complexes could be detected. Conclusion: While the phenomenon of missing data unavoidably complicates EMAP data, our results showed that we could complete the original dataset by the Soft-SVD approach to accurately recover genetic interactions. [Copyright &y& Elsevier]

Contractile properties of skinned muscle fibres from the masseter muscle and strips of heart atrium muscle from rabbits, both containing the α-cardiac myosin heavy chain isoform (α-cardiac MHC), were investigated and compared with those of other skeletal muscle fibre types. The stretch-induced delayed force increase (stretch activation) was investigated on maximally Ca2+-activated skinned preparations as an index of the kinetic properties of the myosin heads of various MHC isoforms. Skeletal muscle fibres containing exclusively α-cardiac MHC (type α) and muscle strips of heart atrium showed specific kinetics of stretch activation intermediate between those of types IIA and I fibres. In agreement with available data the unloaded shortening velocity Vu of type α fibres was also intermediate between that of types IIA and I fibres. Compared with skeletal muscle type α fibres, muscle strips of heart atrium exhibited significantly (P<0.001) faster kinetics of both stretch activation and Vu. We conclude that type α fibres have characteristic kinetic properties that fill the gap between the fast type II and the slow type I fibres, and the following order of velocity can be established: IIB>IID(X)>IIA>α>I. [ABSTRACT FROM AUTHOR]

DNA methylation is an important regulator of gene expression that can influence tumor heterogeneity and shows weak and varying expression levels among different genes. Gastric cancer (GC) is a highly heterogeneous cancer of the digestive system with a high mortality rate worldwide. The heterogeneous subtypes of GC lead to different prognoses. In this study, we explored the relationships between DNA methylation and gene expression levels by introducing a sparse low-rank regression model based on a GC dataset with 375 tumor samples and 32 normal samples from The Cancer Genome Atlas database. Differences in the DNA methylation levels and sites were found to be associated with differences in the expressed genes related to GC development. Overall, 29 methylation-driven genes were found to be related to the GC subtypes, and in the prognostic model, we explored five prognoses related to the methylation sites. Finally, based on a low-rank matrix, seven subgroups were identified with different methylation statuses. These specific classifications based on DNA methylation levels may help to account for heterogeneity and aid in personalized treatments. [ABSTRACT FROM AUTHOR]

Unsupervised band selection has gained increasing attention recently since massive unlabeled high-dimensional data often need to be processed in the domains of machine learning and data mining. This paper presents a novel unsupervised HSI band selection method via band grouping and adaptive multi-graph constraint. A band grouping strategy that assigns each group different weights to construct a global similarity matrix is applied to address the problem of overlooking strong correlations among adjacent bands. Different from previous studies that are limited to fixed graph constraints, we adjust the weight of the local similarity matrix dynamically to construct a global similarity matrix. By partitioning the HSI cube into several groups, the model is built with a combination of significance ranking and band selection. After establishing the model, we addressed the optimization problem by an iterative algorithm, which updates the global similarity matrix, its corresponding reconstruction weights matrix, the projection, and the pseudo-label matrix to ameliorate each of them synergistically. Extensive experimental results indicate our method outperforms the other five state-of-the-art band selection methods in the publicly available datasets. [ABSTRACT FROM AUTHOR]

Multimodal path queries over transportation networks are receiving increasing attention due to their widespread applications. A multimodal path query consists of finding multimodal journeys from source to destination in transportation networks, including unrestricted walking, driving, cycling, and schedule-based public transportation. Transportation networks are generally continent-sized. This characteristic highlights the need for parallel computing to accelerate multimodal path queries. Meanwhile, transportation networks are often fragmented and distributively stored on different machines. This situation calls for exploiting parallel computing power for these distributed systems. Therefore, in this paper, we study distributed multimodal path (DMP) queries over large transportation networks. We develop algorithms to explore parallel computation. When evaluating a DMP query $Q$ Q on a distributed multimodal graph $Gmult$ G m u l t , we show that the algorithms possess the following performance guarantees, irrespective of how $Gmult$ G m u l t is fragmented and distributed: (1) each machine is visited only once; (2) the total network traffic is determined by the size of $Q$ Q and the fragmentation of $Gmult$ G m u l t ; (3) the response time is decided by the largest fragment of $Gmult$ G m u l t ; and (4) the algorithm is parallel scalable. Using real-life and synthetic data, we experimentally verify that the algorithms are scalable on large graphs. [ABSTRACT FROM AUTHOR]

Through silicon via (TSV) is a kind of three-dimensional (3D) packaging technology with great development potential, which can realize short distance electrical interconnection. Currently, there were few related studies on filling or thermal reliability of SAC305-TSV. Because of its thermal expansion coefficient and other physical property parameters do not match with other materials involved in TSV and the crystal structure characteristics of Sn, SAC305-TSV has service reliability problems under the action of thermal load. In this paper, by adding different contents of SiC nanoparticles to SAC305, the performance of SAC305 was improved, and the composite solder with better comprehensive performance was obtained. Besides, the thermal reliability of TSV filled with composite solder was analyzed by thermal shock and aging test with SEM and EBSD. [ABSTRACT FROM AUTHOR]

The Cu-Sn full intermetallic compound is a promising high-temperature electronic packaging material, while its preparation is usually time-consuming. In this work, a novel dual-beam laser co-deposition method was proposed to prepare Cu-Sn nanoparticle film for power electronic packaging with high bonding efficiency. Various Cu-Sn contents were prepared to reveal the bonding mechanism of the full intermetallic compound structure. The results show that joints with a Cu content ranging from 20 wt% to 80 wt% could form full intermetallic compounds within 2 min with the shear strength reaching 120 MPa. Specifically, Cu 6 Sn 5 , 'island-like' Cu 3 Sn, and sintered Cu generated successively in the bondline center with the increasing Cu content. All failures occurred within the bondline indicating a higher interface bonding quality, while the 'island-like' Cu 3 Sn enhanced the shear strength. This die attach process is compatible with current commercial SiC die attach process with lower material cost as well as high efficiency, enabling the Cu-Sn nanoparticle film to be a promising material for high-reliability power electronic packaging. [Display omitted] • Cu-Sn nanoparticle films were prepared by dual-beam laser co-deposition method. • The as-deposited film consisted of Cu, Sn, Cu-Sn nanoalloy, Cu 6 Sn 5 and Cu 3 Sn. • The full IMC joints can be prepared at 280 0C within 2 min. • The shear strength of the full IMC joint reached 120 MPa. [ABSTRACT FROM AUTHOR]

Background: Discoidin, CUB, and LCCL domain-containing type I (DCBLD1) is identified as an oncogene involved in multiple regulation of tumor progression, but specific mechanisms remain unclear in cervical cancer. Lactate-mediated lactylation modulates protein function. Whether DCBLD1 can be modified by lactylation and the function of DCBLD1 lactylation are unknown. Therefore, this study aims to investigate the lactylation of DCBLD1 and identify its specific lactylation sites. Herein, we elucidated the mechanism by which lactylation modification stabilizes the DCBLD1 protein. Furthermore, we investigated DCBLD1 overexpression activating pentose phosphate pathway (PPP) to promote the progression of cervical cancer. Methods: DCBLD1 expression was examined in human cervical cancer cells and adjacent non-tumorous tissues using quantitative reverse transcription-polymerase chain reaction, western blotting, and immunohistochemistry. In vitro and in vivo studies were conducted to investigate the impact of DCBLD1 on the progression of cervical cancer. Untargeted liquid chromatography-tandem mass spectrometry (LC–MS/MS) metabolomics studies were used to characterize DCBLD1-induced metabolite alterations. Western blot, immunofuorescence and transmission electron microscopy were performed to detect DCBLD1 degradation of G6PD by activating autophagy. Chromatin immunoprecipitation, dual luciferase reporter assay for detecting the mechanism by which lactate increases DCBLD1 transcription. LC–MS/MS was employed to verify specific modification sites within the DCBLD1 protein. Results: We found that lactate increased DCBLD1 expression, activating the PPP to facilitate the proliferation and metastasis of cervical cancer cells. DCBLD1 primarily stimulated PPP by upregulating glucose-6-phosphate dehydrogenase (G6PD) expression and enzyme activity. The mechanism involved the increased enrichment of HIF-1α in the DCBLD1 promoter region, enhancing the DCBLD1 mRNA expression. Additionally, lactate-induced DCBLD1 lactylation stabilized DCBLD1 expression. We identified DCBLD1 as a lactylation substrate, with a predominant lactylation site at K172. DCBLD1 overexpression inhibited G6PD autophagic degradation, activating PPP to promote cervical cancer progression. In vivo, 6-An mediated inhibition of G6PD enzyme activity, inhibiting tumor proliferation. Conclusions: Our findings revealed a novel post-translational modification type of DCBDL1, emphasizing the significance of lactylation-driven DCBDL1-mediated PPP in promoting the progression of cervical cancer. Schematic illustration of DCBLD1-induced G6PD-mediated reprogramming of PPP metabolism in promoting cervical cancer progression. [ABSTRACT FROM AUTHOR]

Background: We aimed to determine whether and how the combination of acetazolamide and remote ischemic preconditioning (RIPC) reduced the incidence and severity of acute mountain sickness (AMS). Methods: This is a prospective, randomized, open-label, blinded endpoint (PROBE) study involving 250 healthy volunteers. Participants were randomized (1:1:1:1:1) to following five groups: Ripc (RIPC twice daily, 6 days), Rapid-Ripc (RIPC four times daily, 3 days), Acetazolamide (twice daily, 2 days), Combined (Acetazolamide plus Rapid-Ripc), and Control group. After interventions, participants entered a normobaric hypoxic chamber (equivalent to 4000 m) and stayed for 6 h. The primary outcomes included the incidence and severity of AMS, and SpO2 after hypoxic exposure. Secondary outcomes included systolic and diastolic blood pressure, and heart rate after hypoxic exposure. The mechanisms of the combined regime were investigated through exploratory outcomes, including analysis of venous blood gas, complete blood count, human cytokine antibody array, ELISA validation for PDGF-AB, and detection of PDGF gene polymorphisms. Results: The combination of acetazolamide and RIPC exhibited powerful efficacy in preventing AMS, reducing the incidence of AMS from 26.0 to 6.0% (Combined vs Control: RR 0.23, 95% CI 0.07–0.70, P = 0.006), without significantly increasing the incidence of adverse reactions. Combined group also showed the lowest AMS score (0.92 ± 1.10). Mechanistically, acetazolamide induced a mild metabolic acidosis (pH 7.30 ~ 7.31; HCO3− 18.1 ~ 20.8 mmol/L) and improved SpO2 (89 ~ 91%) following hypoxic exposure. Additionally, thirty differentially expressed proteins (DEPs) related to immune-inflammatory process were identified after hypoxia, among which PDGF-AB was involved. Further validation of PDGF-AB in all individuals showed that both acetazolamide and RIPC downregulated PDGF-AB before hypoxic exposure, suggesting a possible protective mechanism. Furthermore, genetic analyses demonstrated that individuals carrying the PDGFA rs2070958 C allele, rs9690350 G allele, or rs1800814 G allele did not display a decrease in PDGF-AB levels after interventions, and were associated with a higher risk of AMS. Conclusions: The combination of acetazolamide and RIPC exerts a powerful anti-hypoxic effect and represents an innovative and promising strategy for rapid ascent to high altitudes. Acetazolamide improves oxygen saturation. RIPC further aids acetazolamide, which synergistically regulates PDGF-AB, potentially involved in the pathogenesis of AMS. Trial registration: ClinicalTrials.gov NCT05023941. [ABSTRACT FROM AUTHOR]

Background: We aimed to determine whether and how the combination of acetazolamide and remote ischemic preconditioning (RIPC) reduced the incidence and severity of acute mountain sickness (AMS). Methods: This is a prospective, randomized, open-label, blinded endpoint (PROBE) study involving 250 healthy volunteers. Participants were randomized (1:1:1:1:1) to following five groups: Ripc (RIPC twice daily, 6 days), Rapid-Ripc (RIPC four times daily, 3 days), Acetazolamide (twice daily, 2 days), Combined (Acetazolamide plus Rapid-Ripc), and Control group. After interventions, participants entered a normobaric hypoxic chamber (equivalent to 4000 m) and stayed for 6 h. The primary outcomes included the incidence and severity of AMS, and SpO2 after hypoxic exposure. Secondary outcomes included systolic and diastolic blood pressure, and heart rate after hypoxic exposure. The mechanisms of the combined regime were investigated through exploratory outcomes, including analysis of venous blood gas, complete blood count, human cytokine antibody array, ELISA validation for PDGF-AB, and detection of PDGF gene polymorphisms. Results: The combination of acetazolamide and RIPC exhibited powerful efficacy in preventing AMS, reducing the incidence of AMS from 26.0 to 6.0% (Combined vs Control: RR 0.23, 95% CI 0.07–0.70, P = 0.006), without significantly increasing the incidence of adverse reactions. Combined group also showed the lowest AMS score (0.92 ± 1.10). Mechanistically, acetazolamide induced a mild metabolic acidosis (pH 7.30 ~ 7.31; HCO3− 18.1 ~ 20.8 mmol/L) and improved SpO2 (89 ~ 91%) following hypoxic exposure. Additionally, thirty differentially expressed proteins (DEPs) related to immune-inflammatory process were identified after hypoxia, among which PDGF-AB was involved. Further validation of PDGF-AB in all individuals showed that both acetazolamide and RIPC downregulated PDGF-AB before hypoxic exposure, suggesting a possible protective mechanism. Furthermore, genetic analyses demonstrated that individuals carrying the PDGFA rs2070958 C allele, rs9690350 G allele, or rs1800814 G allele did not display a decrease in PDGF-AB levels after interventions, and were associated with a higher risk of AMS. Conclusions: The combination of acetazolamide and RIPC exerts a powerful anti-hypoxic effect and represents an innovative and promising strategy for rapid ascent to high altitudes. Acetazolamide improves oxygen saturation. RIPC further aids acetazolamide, which synergistically regulates PDGF-AB, potentially involved in the pathogenesis of AMS. Trial registration: ClinicalTrials.gov NCT05023941. [ABSTRACT FROM AUTHOR]

Background: Chronic interstitial fibrosis is the primary barrier against the long-term survival of transplanted kidneys. Extending the lifespan of allografts is vital for ensuring the long-term health of patients undergoing kidney transplants. However, few targets and their clinical applications have been identified. Moreover, whether dyslipidemia facilitates fibrosis in renal allograft remains unclear. Methods: Blood samples were collected from patients who underwent kidney transplantation. Correlation analyses were conducted between the Banff score and body mass index, and serum levels of triacylglycerol, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol. A rat model of renal transplantation was treated with the lipid-lowering drug, fenofibrate, and kidney fibrosis levels were determined by histochemical staining. Targeted metabolomic detection was conducted in blood samples from patients who underwent kidney transplantation and were divided into fibrotic and non-fibrotic groups. Rats undergoing renal transplantation were fed either an n-3 or n-6 polyunsaturated fatty acid (PUFA)-enriched diet. Immunohistochemical and Masson's trichrome staining were used to determine the degree of fibrosis. Results: Hyperlipidemia was associated with fibrosis development. Treatment with fenofibrate contributed to improve fibrosis in a rat model of renal transplantation. Moreover, n-3 PUFAs from fibrotic group showed significant downregulation compared to patients without fibrotic renal allografts, and n-3 PUFAs-enriched diet contributed to delayed fibrosis in a rat model of renal transplantation. Conclusions: This study suggests that hyperlipidemia facilitates fibrosis of renal allografts. Importantly, a new therapeutic approach was provided that may delay chronic interstitial fibrosis in transplanted kidneys by augmenting the n-3 PUFA content in the diet. [ABSTRACT FROM AUTHOR]

The treatment of refractory nephrotic syndrome (RNS) is full of challenges and the role of rituximab (RTX) is not well-established, thus this study aims to demonstrate the role of RTX in RNS. This was a multicenter retrospective study of all adult patients receiving RTX for RNS. Patients enrolled were divided into two groups according to pathological pattern: 20 patients as a group of podocytopathy (including minimal change disease [MCD] and focal and segmental glomerulosclerosis [FSGS]), and 26 patients as membranous nephropathy (MN) group. The remission rate, relapse rate, adverse effects, and predictors of remission were analyzed. A total of 75 patients received RTX for RNS and 48 were available for analysis after exclusion criteria. No significant difference in the remission rate at 6 or 12 months was observed between the MCD/FSGS and MN cases (p > 0.05). The median duration of the first complete remission (CR) was 1 month in the podocytopathy group and 12.5 months in the MN group. Three relapses were associated with infection as the ultimate outcome, and 6 out of 48 remained refractory representing a response rate of 87.5% in RNS. Clinical predictors of cumulative CR were estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 and mean arterial pressure (MAP) ≤103 mmHg at the beginning of therapy in patients with MN. No serious adverse effects were reported. RTX appears to be effective in RNS across various clinical and pathological subtypes, exhibiting a low relapse rate and minimal significant side effects in the majority of patients. [ABSTRACT FROM AUTHOR]

Background: Depression is a major risk factor for the morbidity and mortality of cardiovascular disease. A transtheoretical model-based intervention and motivational interviewing have been used to change health risk behaviors and have demonstrated positive effects. To our knowledge, no studies of patients with coronary heart disease (CHD) have used a transtheoretical model-based intervention and motivational interviewing as an intervention to provide dynamic education. Therefore, this study aimed to determine the effects of the transtheoretical model-based intervention and motivational interviewing on the management of depression in hospitalized patients with CHD.Method: A randomized controlled trial was designed. A total of 110 participants were randomly divided into an intervention group (n = 55) and a control group (n = 55). The Hamilton Rating Scale for Depression and the Depression Prevention & Management Survey items (stages of change, perceived benefits, perceived barriers, process of change and self-efficacy) were used to collect data at all time points. Analysis of covariance, chi-square test and repeated measures analysis of variance were used to analyze the data.Results: After the intervention, there were more positive changes in stages of change, higher scores for the cognitive and behavioral levels, the perceived benefits, and self-efficacy, and lower perceived barriers and depression in the intervention group than in the control group. Finally, there were statistically significant differences in the depression scores at different time points in the intervention group (F = 17.814, p = 0.000 < 0.01).Conclusions: The study showed that a transtheoretical model-based intervention and motivational interviewing exert positive effects on the management of depression in hospitalized patients with CHD.Trial Registration: Clinicaltrials.gov, NCT03953924 (Date assigned: 16/5/2019). Retrospectively registered. [ABSTRACT FROM AUTHOR]

The recovery of gold (Au) from waste printed circuit boards (WPCBs) derived from discarded mobile phones is crucial for the resource preservation and environmental protection. In this context, thiosulfate has emerged as a viable alternative to the toxic compound cyanide for Au leaching. However, the conventional thiosulfate leaching system has a main problem that is large thiosulfate consumption, which limits its commercial application. In this study, we developed a novel thiosulfate leaching system that utilizes a cobalt (Co(II))-glycine (gly) complex as the catalyst. Our findings demonstrate that the Co(II)-glycine-thiosulfate system exhibits excellent Au leaching performance coupled with low thiosulfate consumption. The effects of several parameters on Au leaching efficiencies and thiosulfate consumption were investigated. Increasing the concentrations of Co(II), thiosulfate, or glycine was beneficial to the Au leaching. However, increasing temperature promoted the oxidative decomposition of thiosulfate and reduced cobalt stability, negatively impacting Au leaching. Additionally, small amounts of base metals remained after pretreatment of WPCBs using HCl system and H 2 SO 4 -H 2 O 2 system. Therefore, the roasting-assisted leaching process eliminated the adverse effects of these impurity metals and further improved Au leaching efficiency to 97.8% while also decreased thiosulfate consumption. The recovery of Au from the pregnant leach solution was also studied, and our findings demonstrated that N1923 can efficiently extract Au from the solution through anion exchange. Our study developed a novel and efficient Au thiosulfate leaching system catalyzed by the Co(gly) 3 /Co(S 2 O 3) 3 4− redox couple, and put forward a promising approach to enhance Au recyclability from WPCBs while significantly reducing thiosulfate consumption. • Novel Co(II)-glycine-thiosulfate system for Au recovery from WPCBs was developed. • Glycine stabilizes Co(II) to form stable complexes that catalyze Au leaching. • The catalytic mechanism of cobalt-glycine complexes was further studied. • Low redox potential of Co(III)/Co(II) effectively reduces thiosulfate consumption. • A complete gold recovery process was established. [ABSTRACT FROM AUTHOR]

Background: Epistatic miniarray profile (EMAP) studies have enabled the mapping of large-scale genetic interaction networks and generated large amounts of data in model organisms. One approach to analyze EMAP data is to identify gene modules with densely interacting genes. In addition, genetic interaction score (S score) reflects the degree of synergizing or mitigating effect of two mutants, which is also informative. Statistical approaches that exploit both modularity and the pairwise interactions may provide more insight into the underlying biology. However, the high missing rate in EMAP data hinders the development of such approaches. To address the above problem, we adopted the matrix decomposition methodology "low-rank and sparse decomposition" (LRSDec) to decompose EMAP data matrix into low-rank part and sparse part.Results: LRSDec has been demonstrated as an effective technique for analyzing EMAP data. We applied a synthetic dataset and an EMAP dataset studying RNA-related processes in Saccharomyces cerevisiae. Global views of the genetic cross talk between different RNA-related protein complexes and processes have been structured, and novel functions of genes have been predicted. [ABSTRACT FROM AUTHOR]

Premature ovarian insufficiency (POI) is an important cause of infertility and also cause menopausal symptoms, which greatly reduced the quality of life for women. Hormone replacement therapy (HRT), as an important strategy, improved the quality of life for patients, however, the role of HRT in promoting fertility remains controversial. Therefore, seeking an optimal regime for POI becomes more urgent. In this study, we established POI model induced by CTX and BUS and utilized bone marrow derived mesenchymal stem cells (BM-MSCs) transplantation to treat the POI. We found that the decrease of estrogen and the increase of FSH induced by administration of CTX and BUS were rescued by BM-MSC transplantation. H&E staining and TUNEL assay showed that there were more healthy ovarian follicles and less apoptosis of ovarian cells after treatment with BM-MSCs. Further studies showed that there was an obvious decrease of Bax, p53, and p21 after transplantation, however, CyclinD2 was increased. In conclusion, our results demonstrated that BM-MSCs could restore injured ovarian function. Inhibiting apoptosis and promoting residual ovarian cell proliferation may contribute to the process. [ABSTRACT FROM AUTHOR]

In this paper, we propose a novel multimodal retrieval model based on the Extreme Learning Machine (ELM). We exploit two multimedia modalities, the image and text, to achieve the multimodal retrieval. To begin with, we employ the probabilistic Latent Semantic Analysis (pLSA) to respectively simulate the generating processes of texts and images. So we obtain the appropriate representations of the images and those of the texts. Furthermore, ELM is used for training the correlation between the representations of the images and those of the texts. So the multimodal retrieval is implemented by the learned single-hidden layer feedforward neural networks (SLFNs). Additionally, the binary classifiers are trained to improve the accuracy of the multimodal retrieval model. This multimodal model can easily be extended into other modalities and extensive experimental results demonstrate the effectiveness and efficiency of this model based on ELM. [ABSTRACT FROM AUTHOR]

The one-dimensional compressibility of granular materials is investigated analytically in the framework of micromechanics and simulated using the discrete element method. The results show that the oedometric modulus can be expressed in terms of the material properties of particles and fabric-related variables. By relating the coordination number to different quantities, two forms of the compression curve equations are discussed. [ABSTRACT FROM AUTHOR]

The authors compared the effectiveness of thiazide diuretic (TD), angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), and calcium channel blocker (CCB) monotherapies for the treatment of nondiabetic hypertension using MarketScan Databases 2010-2014. Multivariable Cox regression models assessed whether the addition of a new antihypertensive drug, treatment discontinuation, or switch and major cardiovascular or cerebrovascular events varied across groups. A total of 565 009 patients started monotherapy with ACEIs (43.6%), CCBs (23.6%), TDs (18.8%), or ARBs (14.0%). Patients who took TDs had a higher risk for either drug addition or discontinuation than patients who took ACEIs (hazard ratio [HR], 0.69 [95% CI, 0.68-0.70] vs HR, 0.81 [95% CI, 0.80-0.81]), ARBs (HR, 0.67 [95% CI, 0.66-0.68] vs HR, 0.66 [95% CI, 0.65-0.67]), and CCBs (HR, 0.85 [95% CI, 0.84-0.87] vs HR, 0.94 [95% CI, 0.93-0.95]). Conversely, patients who took TDs experienced a lower risk of clinical events compared with patients who took ACEIs (HR, 1.24 [95% CI, 1.15-1.33]), ARBs (HR, 1.28 [95% CI, 1.18-1.39]), and CCBs (HR, 1.35 [95% CI, 1.25-1.46]). Our results provide a strong rationale for choosing TDs as first-line monotherapy for the control of hypertension. [ABSTRACT FROM AUTHOR]

This study investigates the structural, mechanical, and thermodynamic behaviors of AlSi 2 Sc 2 under uniaxial tensile loading by performing first-principles calculations based on density functional theory. The parameters of the lattice a and c were found to depend on the Al–Si and the Sc–Si bonds, respectively. Tensile stress–strain curves were used to obtain ideal tensile strengths of 16.1 GPa and 21.2 GPa along the a- and c -axes, respectively. The criteria for stability showed that the AlSi 2 Sc 2 compound became mechanically unstable when the strain exceeded 0.1 and 0.3 along the a - and the c -axes, respectively. The polycrystalline elastic constants of AlSi 2 Sc 2 decreased with increasing strain along both axes as well, as did its Debye temperature and minimum thermal conductivity. An analysis of its electronic structure indicated that the Al–Si bonds mainly originated from the hybridization of the Al-3p and the Si-3p states, whereas the Sc–Si bonds originated from the S c- 3d and Si-3p states. • The ideal tensile strengths for AlSi 2 Sc 2 along the a and c axis direction are 16.1 GPa and 21.2 GPa, respectively. • The elastic moduli and thermodynamic properties of AlSi 2 Sc 2 compound are decreasing with the increasing of strain. • The Al–Si bonds are originated from Al-2p and Si-2p states, whereas Sc–Si bonds are contributed by Sc-3d and Si-2p states. [ABSTRACT FROM AUTHOR]

In this paper, we proposed a method of strengthening Sn-based solder to retard the microstructural evolution during thermal cycling and thus to improve the thermal fatigue life of Sn-based solder joint. We fabricated a multiple-elemental Sn-based solder by adding Ni, Bi and Sb into the Sn3.0%Ag0.5%Cu (SAC305) solder. Thermal cycling tests (− 55 °C ~ 150 °C) were performed on the prepared multiple-elemental Sn-based solder joints and SAC305 solder joints, and quasi-in situ observation was accompanied by the thermal cycling test to identify and compare the corresponding microstructural evolution process. It turned out that the intragranular dislocation movements were effectively hindered at the early stage of thermal cycling, which was due to the effects of solid solution strengthening. Furthermore, the motion of pre-existing grain boundaries and hysteresis of dislocation slip played a predominated role in the strengthened multiple-elemental solder joints. By contrast, the aforementioned two phenomena occurred concurrently in the non-strengthened solder joints. As a consequence, the multiple-elemental solder joints retained the integrity of solder joints after 1200 thermal cycles. This phenomenon indicates that the microstructural evolution was significantly delayed compared with the pristine SAC305 solder joints during thermal cycling. Therefore, SACNSB solder joints have a longer thermal fatigue life. The idea of retarding microstructure evolution during thermal cycling by strengthening Sn matrix can help open a new pathway to improve thermal fatigue life of Sn-based solder joints. [ABSTRACT FROM AUTHOR]

Background: Cemented and uncemented fixation are the primary methods of tibial prosthesis fixation in total knee arthroplasty. However, the optimal fixation method remains controversial. This article explored whether uncemented tibial fixation has better clinical and radiological outcomes, fewer complications, and revision rates compared to cemented tibial fixation. Methods: We searched the PubMed, Embase, Cochrane Library, and Web of Science databases up to September 2022 to identify randomized controlled trials (RCTs) that compared uncemented total knee arthroplasty (TKA) and cemented TKA. The outcome assessment consisted of clinical and radiological outcomes, complications (aseptic loosening, infection, and thrombosis), and revision rate. Subgroup analysis was used to explore the effects of different fixation methods on knee scores in younger patients. Results: Nine RCTs were finally analyzed with 686 uncemented knees and 678 cemented knees. The mean follow-up time was 12.6 years. The pooled data revealed significant advantages of uncemented fixations over cemented fixations in terms of the Knee Society Knee Score (KSKS) (p = 0.01) and the Knee Society Score–Pain (KSS–Pain) (p = 0.02). Cemented fixations showed significant advantages in maximum total point motion (MTPM) (p < 0.0001). There was no significant difference between uncemented fixation and cemented fixation regarding functional outcomes, range of motion, complications, and revision rates. When comparing among young people (<65 years), the differences in KSKS became statistically insignificant. No significant difference was shown in aseptic loosening and the revision rate among young patients. Conclusions: The current evidence shows better knee score, less pain, comparable complications and revision rates for uncemented tibial prosthesis fixation, compared to cemented, in cruciate-retaining total knee arthroplasty. [ABSTRACT FROM AUTHOR]

In this research, we aimed to perform a comprehensive bioinformatic analysis of immune cell infiltration in osteoarthritic cartilage and synovium and identify potential risk genes. Datasets were downloaded from the Gene Expression Omnibus database. We integrated the datasets, removed the batch effects and analyzed immune cell infiltration along with differentially expressed genes (DEGs). Weighted gene co-expression network analysis (WGCNA) was used to identify the positively correlated gene modules. LASSO (least absolute shrinkage and selection operator)-cox regression analysis was performed to screen the characteristic genes. The intersection of the DEGs, characteristic genes and module genes was identified as the risk genes. The WGCNA analysis demonstrates that the blue module was highly correlated and statistically significant as well as enriched in immune-related signaling pathways and biological functions in the KEGG and GO enrichment. LASSO-cox regression analysis screened 11 characteristic genes from the hub genes of the blue module. After the DEG, characteristic gene and immune-related gene datasets were intersected, three genes, PTGS1, HLA-DMB and GPR137B, were identified as the risk genes in this research. In this research, we identified three risk genes related to the immune system in osteoarthritis and provide a feasible approach to drug development in the future. [ABSTRACT FROM AUTHOR]

Two years ago, the patient's serum immunofixation electrophoresis revealed a monoclonal protein with an IgG- . Acute kidney injury due to thrombotic microangiopathy in a patient with primary Sjögren's syndrome Dear Editor, We described a case of monoclonal gammopathy-associated renal thrombotic microangiopathy (TMA) in a primary Sjögren's syndrome (pSS) patient and who was successfully treated with a bortezomib-based regimen. Her blood urea nitrogen was 18.31 mmol/L, serum creatinine (Scr) was 653 mol/L. Hypercoagulability workup revealed a high level of fibrinogen but negative anti-cardiolipin antibody immunoglobulin (Ig) G and IgM. [Extracted from the article]

Mixed Lineage Leukemia rearranged acute myeloid leukemia (MLLr AML) predicts a poor prognosis. Histone demethylase JMJD1C is a potential druggable target of MLLr AML. However, little is known about how JMJD1C contributes to MLLr AML. Here we found that JMJD1C regulates lipid synthesis-associated genes including FADS2, SCD in MLLr AML cells. Lipid synthesis-associated protein FABP5 was identified as a specific interacting protein of JMJD1C and binds to the jumonji domain of JMJD1C. FABP5 also regulates JMJD1C mRNA and protein expression. JDI-10, a small molecular inhibitor of JMJD1C identified by us, represses MLLr AML cells, induces apoptosis, and decreases JMJD1C-regulated lipid synthesis genes. Moreover, JDI-10 mediated suppression of MLLr AML cells can be rescued by palmitic acid, oleic acid, or recombinant FABP5. In summary, we identified that JMJD1C-regulated lipid synthesis contributes to the maintenance of MLLr AML. Lipid synthesis repression may represent a new direction for the treatment of MLLr AML. [ABSTRACT FROM AUTHOR]

Background: The two major obstacles in the successful transplantation of islets for diabetes treatment are inadequate supply of insulin-producing tissue and immune rejection. Induction of the differentiation of human bone marrow-derived mesenchymal stem cells (hMSCs) into insulin-producing cells (IPCs) for autologous transplantation may alleviate those limitations. Methods: hMSCs were isolated and induced to differentiate into IPCs through a three-stage differentiation protocol in a defined media with high glucose, nicotinamide, and exendin-4. The physiological characteristics and functions of IPCs were then evaluated. Next, about 3 × 106 differentiated cells were transplanted into the renal sub-capsular space of streptozotocin (STZ)-induced diabetic nude mice. Graft survival and function were assessed by immunohistochemistry, TUNEL staining and measurements of blood glucose levels in the mice. Results: The differentiated IPCs were characterized by Dithizone (DTZ) positive staining, expression of pancreatic β-cell markers, and human insulin secretion in response to glucose stimulation. Moreover, 43% of the IPCs showed L-type Ca2+ channel activity and similar changes in intracellular Ca2+ in response to glucose stimulation as that seen in pancreatic β-cells in the process of glucose-stimulated insulin secretion. Transplantation of functional IPCs into the renal subcapsular space of STZ-induced diabetic nude mice ameliorated the hyperglycemia. Immunofluorescence staining revealed that transplanted IPCs sustainably expressed insulin, c-peptide, and PDX-1 without apparent apoptosis in vivo. Conclusions: IPCs derived from hMSCs in vitro can ameliorate STZ-induced diabetic hyperglycemia, which indicates that these hMSCs may be a promising approach to overcome the limitations of islet transplantation. [ABSTRACT FROM AUTHOR]

Despite the confirmed role of LKB1 in suppressing lung cancer progression, its precise effect on cellular senescence is unknown. The aim of this research was to clarify the role and mechanism of LKB1 in restraining telomerase activity in lung adenocarcinoma. The results showed that LKB1 induced cellular senescence and apoptosis either in vitro or in vivo. Overexpression of LKB1 in LKB1-deficient A549 cells led to the inhibition of telomerase activity and the induction of telomere dysfunction by regulating telomerase reverse transcriptase (TERT) expression in terms of transcription. As a transcription factor, Sp1 mediated TERT inhibition after LKB1 overexpression. LKB1 induced lactate production and inhibited histone H4 (Lys8) and H4 (Lys16) lactylation, which further altered Sp1-related transcriptional activity. The telomerase inhibitor BIBR1532 was beneficial for achieving the optimum curative effect of traditional chemotherapeutic drugs accompanied by the glycolysis inhibitor 2DG. These data reveal a new mechanism by which LKB1 regulates telomerase activity through lactylation-dependent transcriptional inhibition, and therefore, provide new insights into the effects of LKB1-mediated senescence in lung adenocarcinoma. Our research has opened up new possibilities for the creation of new cancer treatments. LKB1 induced cellular senescence through the inhibition of telomerase activity and the induction of telomere dysfunction by regulating telomerase reverse transcriptase (TERT) expression in terms of transcription. Mechanistically, LKB1 reduces lactate production and inhibits histone H4 (Lys8) and H4 (Lys16) lactalytion, which further altered Sp1-related transcriptional activity especially TERT transcription. Telomere dysfunction activates DNA damage response and influences p53 related cellular senescence. However, p53 and p21 mediated G1 cell cycle arrest might provide an opportunity for telomerase-mediated telomere extension. Therefore, inhibiting telomerase activity and inducing LKB1-induced cellular senescence at the same time might be a valuable new treatment strategy to improve the outcome. [Display omitted] [ABSTRACT FROM AUTHOR]

Accumulated alterations in metabolic control provide energy and anabolic demands for enhanced cancer cell proliferation. Exemplified by the Warburg effect, changes in glucose metabolism during cancer progression are widely recognized as a characteristic of metabolic disorders. Since telomerases are a vital factor in maintaining DNA integrity and stability, any damage threatening telomerases could have a severe impact on DNA and, subsequently, whole-cell homeostasis. However, it remains unclear whether the regulation of glucose metabolism in cancer is connected to the regulation of telomerase. In this review, we present the latest insights into the crosstalk between telomerase function and glucose metabolism in cancer cells. However, at this moment this subject is not well investigated that the association is mostly indirectly regulations and few explicit regulating pathways were identified between telomerase and glucose metabolism. Therefore, the information presented in this review can provide a scientific basis for further research on the detail mechanism and the clinical application of cancer therapy, which could be valuable in improving the effectiveness of chemotherapy. [ABSTRACT FROM AUTHOR]