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Abstract As construction technology and project management develop, structural monitoring systems become increasingly important for ensuring large-span spatial structure safety during construction and operation. However, most of the sensors and monitoring equipment in monitoring systems are poorly serviced, resulting in frequent abnormal monitoring data, which directly leads to challenges in data analysis and structural safety assessment. In this paper, a structural response recovery method based on a long short-term memory (LSTM) neural network is proposed by studying the autocorrelation of data and the spatial correlations among data at multiple measurement points. The effectiveness and robustness of the proposed method are verified using the monitored stress data for a grid structure jacking construction process, and the influence of different data loss rates on the recovery accuracy is analysed. The recovery models are compared using a support vector machine and a Multi-Layer Perception (MLP) neural network. The proposed method can effectively restore missing data; notably, the MSE index is 0.6, and the MAPE is below 15%. The data restoration method based on the LSTM neural network is more accurate than the traditional method. Finally, the repair applicability of various types of monitored data is verified using the monitoring data from Hall F of Qingdao Jiao-dong International Airport under typhoon conditions.

In this study, we discovered that a certain concentration of Na+ (15 mM) significantly improved the bond strength (12.94 ± 0.93 MPa), thermal stability (72.68 °C), rheological properties, and textural attributes of walnut protein isolate (WNPI)-κ-carrageenan (KC) composite gel. Electrostatic force, hydrophobic interaction, hydrogen bond, and disulfide bond were also significantly strengthened; the α-helix decreased, and the β-sheet increased in the secondary structure, indicating that the protein molecules in the gel system aggregated in an orderly manner, which led to a much denser and more uniform gel network as well as improved water-holding capacity. In this experimental research, we developed a new type of walnut protein gel that could provide technical support for the high-value utilization and quality control of walnut protein.

BACKGROUND:Pregnane X receptor (PXR) regulates the expression of drug-metabolizing enzymes and transport enzymes. NF-κB not only plays a role in liver homeostasis and injury-healing processes by regulating inflammatory responses but may also regulate the transcription of PXR. Currently, genetic polymorphisms in PXR are associated with adverse drug effects. Because little is known about the association between NF-κB1 genetic polymorphisms and adverse drug reactions, we explored the association between PXR and NF-κB1 single nucleotide polymorphisms (SNPs) and susceptibility to anti-tuberculosis drug-induced liver injury (ATDILI). MATERIALS AND METHODS:A total of 746 tuberculosis patients (118 with ATDILI and 628 without ATDILI) were prospectively enrolled at West China Hospital between December 2014 and April 2018. Nine selected SNPs (rs3814055, rs13059232, rs7643645 and rs3732360 in PXR and rs78872571, rs4647992, rs60371688, rs1598861 and rs3774959 in NF-κB1) were genotyped with a custom-designed 2x48-plex SNP Scan TM Kit. The frequencies of the alleles, genotypes and genetic models of the variants were compared between patients with or without ATDILI, while joint effect analysis of the SNP-SNP interactions was performed using multiplicative and additive models. The odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were calculated. RESULTS:The T allele of rs3814055 in PXR was associated with a decreased risk for ATDILI (OR 0.61; 95% CI: 0.42-0.89, p = 0.0098). The T alleles of rs78872571 and rs4647992 in NF-κB1 were significantly associated with an increased risk for ATDILI (OR 1.91; 95% CI: 1.06-3.43, p = 0.028 and OR 1.81; 1.06-3.10, p = 0.029, respectively). The allele, genotype and genetic model frequencies were similar in the two groups for the other six SNPs (all P>0.05). There were no multiplicative or additive interactions between the SNPs. CONCLUSION:Our study is the first to reveal that rs3814055 variants in PXR and rs78872571 and rs4647992 variants in NF-κB1 are associated with susceptibility to ATDILI caused by first-line anti-tuberculosis combination treatment in the Han Chinese population.

Venous ulcers are chronic transcutaneous wounds common in the lower legs. They are resistant to healing and have a 78% chance of recurrence within 2 years. It is commonly accepted that venous ulcers are caused by the insufficiency of the calf muscle pump, leading to blood pooling in the lower legs, resulting in inflammation, skin oedema, tissue necrosis and eventually skin ulceration. However, the detailed physiological events by which inflammation contributes to wound formation are poorly understood. We therefore sought to develop a model that simulated the inflammation, using it to determine the internal stresses and pressure on the skin that contribute to venous ulcer formation. A three-layer finite-element skin model (epidermis, dermis and hypodermis) was developed to explore the roles in wound formation of two inflammation identifiers: glycosaminoglycans (GAG) and sodium. A series of parametric studies showed that increased GAG and sodium content led to oedema and increased tissue stresses of 1.5 MPa, which was within the reported range of skin tissue ultimate tensile stress (0.1–40 MPa). These results suggested that both the oedema and increased fluid pressure could reach a threshold for tissue damage and eventual ulcer formation. The models presented here provide insights to the pathological events associated with venous insufficiency, including inflammation, oedema and skin ulceration.

OBJECTIVES:The goal of this research was to evaluate how material curl, package structure and handling of pouches containing medical devices affect rates of contact between non-sterile surfaces and sterile devices during aseptic transfer. METHODS:One hundred and thirty-six individuals with practical experience in aseptic technique were recruited. Participants were asked to present the contents of four different pouch designs (a standard, one designed to curl in, another to curl out and one that incorporated a tab) using two transfer techniques. During the first block of trials "standard technique" was used; participants presented using their typical methods to the sterile field. Trials in the second block employed "modified technique"; participants were instructed to grab the package at the top center and present package contents using a single, fluid motion. The outside of the pouch and the backs of the participants' hands were coated using a simulated contaminant before each trial. The simulant was undetectable in the visible spectrum, but fluoresced under a black light. The dependent variable was recorded in a binary fashion and analyzed using a generalized linear mixed model. RESULTS:Participants were between 20-57 and the averaged year 5.1 years of experience in aseptic technique. The data analysis was based on generalized linear mixed effects (GLMM) model, which accommodates the repeated measurements within the same participant. The effect of the pouch design was significant (P‹0.001), but the effect of aseptic technique did not suggest significance (P = 0.088). Specifically, pouches designed with the material curled outward resulted in significantly fewer contacts with non-sterile surfaces than the other styles, including the inward, tab, and standard styles; this was true regardless of the used aseptic technique, standard (P = 0.0171, P = 0.0466, P = 0.0061, respectively) or modified (P‹0.0001 for all comparisons)). CONCLUSION:Results presented here contribute to a growing body of knowledge that investigates packaging as a potential route of contamination for sterile devices during aseptic presentation. Specifically, we provide insights regarding how both package design and opening technique can be informed in ways that build safety into the healthcare system.

The Banff Digital Pathology Working Group (DPWG) was formed in the time leading up to and during the joint American Society for Histocompatibility and Immunogenetics/Banff Meeting, September 23-27, 2019, held in Pittsburgh, Pennsylvania. At the meeting, the 14th Banff Conference, presentations directly and peripherally related to the topic of "digital pathology" were presented; and discussions before, during, and after the meeting have resulted in a list of issues to address for the DPWG. Included are practice standardization, integrative approaches for study classification, scoring of histologic parameters (eg, interstitial fibrosis and tubular atrophy and inflammation), algorithm classification, and precision diagnosis (eg, molecular pathways and therapeutics). Since the meeting, a survey with international participation of mostly pathologists (81%) was conducted, showing that whole slide imaging is available at the majority of centers (71%) but that artificial intelligence (AI)/machine learning was only used in ≈12% of centers, with a wide variety of programs/algorithms employed. Digitalization is not just an end in itself. It also is a necessary precondition for AI and other approaches. Discussions at the meeting and the survey highlight the unmet need for a Banff DPWG and point the way toward future contributions that can be made.

Integrating two distinct and complementary paradigms, science and engineering, may produce more effective outcomes for the implementation of evidence-based practices in health care settings. Science formalizes and tests innovations, whereas engineering customizes and optimizes how the innovation is applied tailoring to accommodate local conditions. Together they may accelerate the creation of an evidence-based healthcare system that works effectively in specific health care settings. We give examples of applying engineering methods for better quality, more efficient, and safer implementation of clinical practices, medical devices, and health services systems. A specific example was applying systems engineering design that orchestrated people, process, data, decision-making, and communication through a technology application to implement evidence-based depression care among low-income patients with diabetes. We recommend that leading journals recognize the fundamental role of engineering in implementation research, to improve understanding of design elements that create a better fit between program elements and local context.

The risk assessment of science and technology projects could be regarded as a classical multiple attribute group decision-making (MAGDM) issue. The Pythagorean fuzzy sets (PFSs) can fully describe the uncertain information for the risk assessment of science and technology projects. Furthermore, the classical TODIM method based on the cumulative prospect theory (CPT-TODIM) is built, which is a selectable method in reflecting the DMs' psychological behavior. Thus, in this paper, the Pythagorean fuzzy CPT-TODIM (PF-CPT-TODIM) method is proposed for MAGDM issue. At the same time, it is enhancing rationality to get the weight information of attributes by using the entropy weight method under PFSs. And focusing on hot issues in contemporary society, this article applies the discussed method to risk assessment of science and technology projects, and demonstrates risk assessment model of science and technology projects based on the proposed method. Finally, through comparing the outcome of comparative analysis, we conclude that this improved approach is acceptable. [ABSTRACT FROM AUTHOR]

• A novel approach of measuring "risk" in knowledge recombination. • The probability of failing to recombine a pair of knowledge elements is computed. • Based on machine learning and natural language processing techniques. • The calculated risk indicator is confirmed to be correlated with self-assessed risk. • Potential application to a wide range of scientific text data. Risk plays a fundamental role in scientific discoveries, and thus it is critical that the level of risk can be systematically quantified. We propose a novel approach to measuring risk entailed in a particular mode of discovery process – knowledge recombination. The recombination of extant knowledge serves as an important route to generate new knowledge, but attempts of recombination often fail. Drawing on machine learning and natural language processing techniques, our approach converts knowledge elements in the text format into high-dimensional vector expressions and computes the probability of failing to combine a pair of knowledge elements. Testing the calculated risk indicator on survey data, we confirm that our indicator is correlated with self-assessed risk. Further, as risk and novelty have been confounded in the literature, we examine and suggest the divergence of the bibliometric novelty and risk indicators. Finally, we demonstrate that our risk indicator is negatively associated with future citation impact, suggesting that risk-taking itself may not necessarily pay off. Our approach can assist decision making of scientists and relevant parties such as policymakers, funding bodies, and R&D managers. [ABSTRACT FROM AUTHOR]

With the development of science and technology, a series of creative techniques have been proposed in Japan since 1930s. By illustrating some specific creative techniques in Japan, this paper analyzes the regional characteristics of creative techniques in Japan, namely, integration, reformism, locality, operability, specialization and simplicity. A combination of such local knowledge theories as post-colonial scientific views, philosophy of scientific practice and cultural anthropology contributes to an analysis of the regional characteristics of creative techniques in Japan which reflect the local knowledge and methods. The findings suggest that creative techniques with unique Chinese characteristics should be incubated in the Chinese local culture; hereby, the Chinese local culture deserves to be valued. [ABSTRACT FROM AUTHOR]

The thesis explores nonlinear complex relationship between Scientific Advance and Ecological Civilization from the perspective of complexity science, and analyses the critical fluctuating function of scientific advance in the process of ecological change and promoting ecological civilization through discssing ideology of scientific advance and Ecological civilization so as to generalize a conclusion that comlex thinking pattern attributes to constructing fundamental view of scientific advance and ecological civilization. [ABSTRACT FROM AUTHOR]

Abstract Hepatitis B is one of the public health priorities worldwide, especially in the Southwest China. Our study aimed to investigate the relationship between genotypes and drug resistance mutations among HBV patients in Southwest China, with the objective of providing guidance for clinical antiviral treatment. A total of 4266 chronic hepatitis B (CHB) patients treated in the Qianjiang Hospital of Chongqing University were included in our study from 2014 to 2020. Both genotypes and drug-resistant mutations of CHB patients were determined by polymerase chain reaction (PCR). Genotype B and genotype C were the main HBV genotypes in our study. We found 54 mutation patterns, including 9 single-site mutations and 45 multiple-site mutations, accounting for 57.64% and 42.36%, respectively. rtM204I/V/S (485/1936) was the most common single-site mutation type, and rtL180M + rtM204I/V (482/1936) was the most common multiple-site mutation type. 1372 CHB patients were resistant to LAM + LDT, and 342 CHB patients were resistant to ADV. There was only 1 CHB patient who exhibited resistance to LAM + LDT + ADV + ETV, with a specific mutation pattern of rtA181T + rtT184L + rtM204V. Our study demonstrated trends in genetic mutations and drug resistance in CHB patients to enable timely adjustment of antiviral treatment strategies.

Abstract Kindergarten activity rooms benefit children’s growth and development under good natural indoor lighting conditions. Therefore, it is of great significance to conduct research on the indoor daylighting effects of kindergarten activity rooms under different orientations. However, most of the existing studies are based on the analysis and simulation of fixed orientations and single elements, and lack of comprehensive evaluation and analysis. Based on the above problems, this study utilizes China’s light climate data and daylighting standards for kindergartens, and selects Linzhi, Kunming, Zhengzhou, Hangzhou, and Guiyang as the research locations, and comprehensively evaluates the indoor daylighting effects. The results of the study show that: (1) The daylighting effect of kindergarten activity rooms in China’s different light climate zones varies greatly, mainly affected by the daylighting orientation, and the high-quality daylighting orientations of the five cities mainly focuses on the range of 210°–255°; (2) The value of sDA of the five cities is basically more than 75%, the uniformity of daylighting effects has all achieved good or higher standards; (3) Guiyang is the least affected by glare, with the smallest impact time range, while the other four cities are more serious. This study explores the impact of sDA, illuminance, and DGP in kindergarten activity rooms on children. The results provide a valuable baseline and technical reference for the daylighting design of kindergarten activity rooms.

Abstract Large-scale neural recording with single-neuron resolution has revealed the functional complexity of the neural systems. However, even under well-designed task conditions, the cortex-wide network exhibits highly dynamic trial variability, posing challenges to the conventional trial-averaged analysis. To study mesoscale trial variability, we conducted a comparative study between fluorescence imaging of layer-2/3 neurons in vivo and network simulation in silico. We imaged up to 40,000 cortical neurons’ triggered responses by deep brain stimulus (DBS). And we build an in silico network to reproduce the biological phenomena we observed in vivo. We proved the existence of ineluctable trial variability and found it influenced by input amplitude and range. Moreover, we demonstrated that a spatially heterogeneous coding community accounts for more reliable inter-trial coding despite single-unit trial variability. A deeper understanding of trial variability from the perspective of a dynamical system may lead to uncovering intellectual abilities such as parallel coding and creativity.

Abstract Palladium-catalyzed directed C − H functionalization/cyclization is an effective approach for synthesizing nitrogen heterocycles. Imine, known for its ease of installation/removal, has been extensively used in the C–H activation of aldehydes, ketones, and alkylamines. Nevertheless, it has been rarely explored in the C(sp2)–H activation of aryl amines because of the generation of a strained four-membered palladacycle. Herein, an imine directed palladium catalyzed C(sp2)–H functionalization of aryl amines assisted by vinylacetic acid is established, providing access to a variety of γ-lactone fused tetrahydroquinolines under mild reaction conditions. The methodology demonstrates broad substrate scope and good functional group tolerance, representing notable advancement in organic synthesis. Mechanistic experiments are performed to clarify how the C(sp2)–H activation occurs, indicating the crucial role of vinylacetic acid. DFT calculations supports the observations, elucidating the strained four-membered ring C–H activation barrier is overcome via coordination and hydrogen bond interaction of vinylacetic acid.

Abstract Intermetallic phases with atomic ordering are highly active and stable in catalysts. However, understanding the atomistic mechanisms of disorder-to-order phase transition, particularly in multi-component systems, remains challenging. Here, we investigate the atom diffusion and phase transition within Pd@Pt-Co cubic nanoparticles during annealing, using in-situ electron microscopy and ex-situ atomic resolution element analysis. We reveal that initial outward diffusing Pd partially substitutes Pt, forming a (Pt, Pd)-Co ternary system in the surface region, enabling the phase transition at a low temperature of 400 °C, followed by shape-preserved inward propagation of the ordered phase. At higher temperatures, excessive interdiffusion across the interface changes the stoichiometric ratio, diminishing the atomic ordering, leading to obvious change in morphology. Calculations indicate that the Pd-substitute in (Pt, Pd)-Co system leads to a significantly lower phase transition temperature compared to that of Pt-Co alloy and thus a lower activation energy for atomic diffusion. These insights into atomistic behavior are crucial for future design of multi-component systems.

Abstract Relapse is one of the major challenges in clinical treatment of acute myeloid leukemia (AML). Though minimal residual disease (MRD) monitoring plays a crucial role in quantitative assessment of the disease, molecular MRD analysis has been mainly limited to patients diagnosed with gene fusions and NPM1 mutations. Here, we report a longitudinal ultra-sensitive mutation burden (UMB) monitoring strategy for accurate MRD analysis in AML patients regardless of genetic abnormality types. Using a Quantitative Blocker Displacement Amplification (QBDA) sequencing panel with limit of detection below 0.01% variant allele frequency (VAF), a hazard ratio of 14.8 (p

Abstract Based on Chinese Students’ Fitness Health Examination, this study sought to investigate the relationships between depressive symptoms and family environment, physical activity, dietary habits, sleep and sedentary behavior among children and adolescents. A cross-sectional study was carried out to estimate the prevalence of depressive symptoms in 32,389 participants (grades 4–12) using the CES-D. Logistic regression was used to evaluate the relationships between lifestyle determinants and depressive symptoms, and a random forest model was used to rank the importance of those determinants. The overall prevalence of depressive symptoms was 39.93%. Students with depressive symptoms had higher grades, lower parental educational levels and unhealthy lifestyles (P

Abstract This study aimed to evaluate the safety profile and beneficial effects of Heyndrickxia coagulans strain BC99 (BC99) for potential use in functional foods and pharmaceuticals. We began with whole genome sequencing of BC99, followed by a comprehensive safety assessment comprising genome analysis, hemolysis, cytotoxicity, antibiotic susceptibility tests, and cell adhesion and tolerance studies, along with acute and subacute oral toxicity studies in animal models. BC99 was isolated from a well-characterized collection originating from the feces of a healthy infant. Our results indicated no hemolytic activity on Columbia blood agar plates and broad antibiotic sensitivity, including to gentamicin, ampicillin, chloramphenicol, ciprofloxacin, and others. Cytotoxicity testing confirmed no adverse effects on HT-29 cells and significant adhesive properties to intestinal epithelial cells. Tolerance tests demonstrated over 90% viability of BC99 under simulated gastrointestinal conditions. In vivo studies in mice and rats confirmed the absence of adverse effects following oral administration. Collectively, these findings support BC99’s robust tolerance to gastrointestinal environments, strong adhesion capabilities, and a broad spectrum of antibiotic resistance, underlining its potential as a safe and effective agent for gut microbiota modulation and host health enhancement.

Abstract Clear cell renal cell carcinoma (ccRCC) is a common genitourinary malignancy characterized by dysregulated cellular metabolism leading to aberrant glucose metabolism, fatty acid accumulation, and excessive reactive oxygen species production. ccRCC cells exhibit an augmented oxidative stress response. Complex interactions between iron metabolism and lipid homeostasis in ccRCC cells require a counteracting response that enables ferroptosis evasion and survival maintenance. Additionally, abnormal GA-binding protein transcription factor subunit alpha (GABPA) expression is associated with ccRCC occurrence and development, but its impact on ferroptosis-related molecular mechanisms remains unclear. Herein, we examined the impact of the GABPA–ACSL4 pathway on ferroptosis in ccRCC through bioinformatics analysis, as well as in vitro and in vivo experiments. In contrast to that in adjacent normal tissues, GABPA expression was significantly downregulated in ccRCC tissues, and this downregulation was linked to poor overall survival. Increased GABPA expression suppressed ccRCC cell proliferation, migration, and invasion. Moreover, GABPA overexpression increased the susceptibility of ccRCC cells to ferroptosis. Additionally, GABPA directly bound to the promoter region of ACSL4, promoting ferroptosis. Thus, inducing the GABPA–ACSL4 pathway activates ferroptosis, inhibits proliferation or metastasis, and exerts anticancer activity in ccRCC. These findings have important implications for regulating ccRCC occurrence and development.

Abstract RNA methylation is an important regulatory process to determine immune cell function but how it affects the anti-tumor activity of CD8 T cells is not fully understood. Here we show that the N 6-methyladenosine (m6A) RNA reader YTHDF2 is highly expressed in early effector or effector-like CD8 T cells. We find that YTHDF2 facilitates nascent RNA synthesis, and m6A recognition is fundamental for this distinctively nuclear function of the protein, which also reinforces its autoregulation at the RNA level. Loss of YTHDF2 in T cells exacerbates tumor progression and confers unresponsiveness to PD-1 blockade in mice and in humans. In addition to initiating RNA decay that is necessary for mitochondrial fitness, YTHDF2 orchestrates chromatin changes that promote T cell polyfunctionality. YTHDF2 interacts with IKZF1/3, which is important for sustained transcription of their target genes. Accordingly, immunotherapy-induced efficacy could be largely restored in YTHDF2-deficient T cells through combinational use of IKZF1/3 inhibitor lenalidomide in a mouse model. Thus, YTHDF2 coordinates epi-transcriptional and transcriptional networks to potentiate T cell immunity, which could inform therapeutic intervention.

Abstract This study aimed to evaluate the effect of Astragalus polysaccharides (PG2) on reducing chemotherapy-induced fatigue (CIF) and toxicity, thereby encouraging compliance to chemotherapy. This was a randomized, placebo-controlled, phase 2 study. Patients with stage II/III early breast cancer planning to undergo adjuvant anthracycline-based chemotherapy were randomly assigned to receive PG2 500 mg or placebo on days 1, 3, and 8 every 21 days. The fatigue global score (FGS) was assessed using the brief fatigue inventory (BFI)-Taiwan. The Breast Cancer-Specific Module of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaires-Core30 evaluated the health-related quality of life during the first four cycles of adjuvant chemotherapy. Overall, 66 eligible patients were equally randomized into the PG2 and placebo groups between March 01, 2018, and March 09, 2021. The mean change in the FGS and fatigue intensity did not significantly differ between both groups. However, the FGS and fatigue intensity were less aggravated in the first four cycles in the premenopausal-PG2 group than in the placebo group. Our study concluded PG2 combined with adjuvant chemotherapy can reduce CIF, insomnia, the negative effect on future perspectives, and improve global health status, especially for premenopausal patients with breast cancer. Trial registration number: NCT03314805 registered on 19/10/2017.

Abstract Non-alcoholic fatty liver disease (NAFLD) is a major global health concern, with its prevalence increasing steadily. While plasma proteins have been implicated in NAFLD, establishing causal relationships has been challenging due to confounding factors in observational studies. This study aims to explore the causal relationships between plasma proteins and NAFLD using Mendelian randomization (MR) analysis. We utilized genome-wide association study (GWAS) data from multiple sources to conduct MR analyses. Plasma protein data were obtained from the deCODE open database, and NAFLD data were sourced from the Finnish genetic sample collection (FinnGen). We performed MR analysis to identify plasma proteins causally related to NAFLD and explored the potential mediation effect of antibody-immune responses. Our MR analysis identified three plasma proteins—KNG1, MICB, and PKD2—with significant causal relationships to NAFLD. Mediation analysis further revealed that KNG1 negatively mediated the risk of NAFLD through Epstein-Barr virus EA-D antibody levels, while MICB and PKD2 positively mediated NAFLD risk through the same antibody levels. This study provides novel genetic evidence of causal relationships between specific plasma proteins and NAFLD risk. Measuring the levels of KNG1, MICB, PKD2, and Epstein-Barr virus EA-D antibody levels in patients may help clinicians assess NAFLD risk more accurately. Further clinical research is warranted to validate these findings and explore their potential therapeutic implications.

Abstract Ovarian cancer (OC) is one of the most prevalent and lethal malignancies affecting the female reproductive system, due to its tendency for metastasis and recurrence. This study identified the overexpression of LINC01320 (or long intergenic nonprotein coding RNA 1320) in tissues of ovarian cancer through the analysis of patient samples and online datasets. In vitro and in vivo experiments demonstrate that silencing of LINC01320 expression led to inhibition of proliferation and metastasis of OC cells. RNA pull-down followed by liquid chromatography tandem mass spectrometry (RNA pull-down-LC-MS/MS) revealed that LINC01320 interacted with purine-rich element binding protein B (PURB), a transcriptional repressor. Furthermore, the RNA-seq analysis identified damage-specific DNA binding protein 2 (DDB2) as a major common target of LINC01320 and PURB. Mechanistically, LINC01320 could recruit PURB to the promoter region of DDB2 to repress DDB2 transcription; thus, promoting the expression of NEDD4L and impeding the TGF-β/SMAD signaling pathway, and ultimately facilitating the progression of OC. Finally, rescue experiments confirmed the involvement of the DDB2/NEDD4L/TGF-β axis in LINC01320-mediated OC progression. In conclusion, this study unveils for the first time the pivotal function of the LINC01320/PURB/DDB2/NEDD4L/TGF-β axis and explores its prospective clinical implications in OC.

Abstract Generative drug design facilitates the creation of compounds effective against pathogenic target proteins. This opens up the potential to discover novel compounds within the vast chemical space and fosters the development of innovative therapeutic strategies. However, the practicality of generated molecules is often limited, as many designs focus on a narrow set of drug-related properties, failing to improve the success rate of subsequent drug discovery process. To overcome these challenges, we develop TamGen, a method that employs a GPT-like chemical language model and enables target-aware molecule generation and compound refinement. We demonstrate that the compounds generated by TamGen have improved molecular quality and viability. Additionally, we have integrated TamGen into a drug discovery pipeline and identified 14 compounds showing compelling inhibitory activity against the Tuberculosis ClpP protease, with the most effective compound exhibiting a half maximal inhibitory concentration (IC50) of 1.9 μM. Our findings underscore the practical potential and real-world applicability of generative drug design approaches, paving the way for future advancements in the field.

Abstract Metabolic disorder significantly contributes to diabetic vascular complications, including diabetic retinopathy, the leading cause of blindness in the working-age population. However, the molecular mechanisms by which disturbed metabolic homeostasis causes vascular dysfunction in diabetic retinopathy remain unclear. O-GlcNAcylation modification acts as a nutrient sensor particularly sensitive to ambient glucose. Here, we observe pronounced O-GlcNAc elevation in retina endothelial cells of diabetic retinopathy patients and mouse models. Endothelial-specific depletion or pharmacological inhibition of O-GlcNAc transferase effectively mitigates vascular dysfunction. Mechanistically, we find that Yes-associated protein (YAP) and Transcriptional co-activator with PDZ-binding motif (TAZ), key effectors of the Hippo pathway, are O-GlcNAcylated in diabetic retinopathy. We identify threonine 383 as an O-GlcNAc site on YAP, which inhibits its phosphorylation at serine 397, leading to its stabilization and activation, thereby promoting vascular dysfunction by inducing a pro-angiogenic and glucose metabolic transcriptional program. This work emphasizes the critical role of the O-GlcNAc-Hippo axis in the pathogenesis of diabetic retinopathy and suggests its potential as a therapeutic target.

Abstract Background Nonsteroidal anti-inflammatory drugs (NSAIDs) are common drugs in patients with osteoarthritis (OA). NSAIDs are generally used at home by patients, without supervision, requiring proper knowledge and attitudes for correct practice. This study investigated the knowledge, attitude, and practice (KAP) of patients with OA toward NSAIDs. Methods This cross-sectional study enrolled patients with OA at the Qingpu Branch of Zhongshan Hospital of Fudan University between January and March 2024. The KAP scores and demographic information of respondents were collected through a self-designed questionnaire. Results There were 645 participants, with 579 (89.8%) over 45 years old and 394 (61.1%) females. The average scores for knowledge, attitude, and practice were 16.26 ± 3.79 (possible range: 0–24), 18.12 ± 1.99 (possible range: 5–35), and 29.20 ± 5.52 (possible range: 10–50), respectively. The structural equation model (SEM) found that for individuals currently using NSAIDs, the attitude had a direct effect on practice (β = 0.978, P

Abstract Prenatal exposure to perfluoroalkyl and polyfluoroalkyl substances (PFASs) may cause adverse birth outcomes. Thyroid hormones may play a key role in mediating the effects of PFAS. We enrolled 374 mother-infant pairs from the Ezhou birth cohort study between 2019 and 2020. Eight PFASs and six thyroid hormones were measured in maternal serum during the first trimester of pregnancy. Neonatal growth metrics, including birth weight, length, head circumference, and gestational age, were acquired. Multivariate linear regression was performed to determine the associations between maternal serum PFAS and thyroid hormone levels and birth outcomes and a mediation analysis was also conducted. Except for perfluoroheptanoic acid (41.2%), the other seven PFAS detection rates were more than 85%, and the highest median concentration was observed for PFOSA with levels of 5.21 ng/mL. After controlling for typical confounders, we observed a decrease in birth length (cm) with increasing serum concentrations of perfluorononanoic acid (PFNA) (β = -0.54; 95% CI = -1.0, -0.08) and perfluorohexane sulfonate (PFHxS) (β = -0.64; 95% CI = -0.86, -0.42). Additionally, a decrease in birth head circumference was observed with increasing concentrations of perfluorooctanote (PFOA) (β = -0.73, 95% CI = -1.19, -0.27) and PFHxS (β = -0.30; 95% CI = -0.53, -0.07). Maternal free triiodothyronine (FT3) mediated 36.7% of the negative association between PFNA and birth length, and free thyroxine (FT4) mediated 30.8% of the effect of PFOA on head circumference. When performing stratified analysis by infant sex, the associations might differ between boys and girls. Our study suggested prenatal exposure to some PFASs was negatively associated with birth length and circumference, and FT3 and FT4 may partly mediate the association.

Abstract Osteosarcoma (OS) is a cancerous tumor, and its development is greatly influenced by long non-coding RNA (lncRNA). Endoplasmic reticulum stress (ERS) is an essential biological defense process in cells and contributes to the progression of tumors. However, the exact mechanisms remain elusive. This study aims to develop a signature of lncRNAs associated with ERS in OS. This signature will guide the prognosis prediction and the determination of appropriate treatment strategies. The UCSC Xena database collected transcriptional and clinical data of OS and muscle, after identifying ERS differentially expressed genes, we utilized correlation analysis to determine the endoplasmic reticulum stress lncRNAs (ERLs). The Least Absolute Shrinkage and Selection Operator (LASSO) and Cox regression analysis were utilized to develop an ERLs signature. To clarify the fundamental mechanisms controlling gene expression in low and high-risk groups, Gene Set Variation Analysis (GSVA) were conducted. In addition, the distinction between the two groups regarding drug sensitivity and immune-related activity was investigated to determine the immunotherapy effects. Utilizing RT-qPCR, the expression of model lncRNAs in OS cell lines was ascertained. The functional analysis of LINC02298 was carried out through in vitro experiments and pan-cancer analysis. This study successfully constructed an ERLs prognostic signature for OS, which comprised 5 lncRNAs (AC023157.3, AL031673.1, LINC02298, LINC02328, SNHG26). The risk signature predicted overall survival in patients with OS and was confirmed by assessing the validation and whole cohorts. Further, it was discovered that individuals classified as high-risk displayed suppressed immune activation, decreased infiltration of immune cells, and decreased responsiveness to immunotherapy. The RT-qPCR showed that the constructed risk prognosis model is reliable. Experimental validation has demonstrated that LINC02298 can promote OS cells’ invasion, migration, and proliferation. In addition, LINC02298 exhibited significant differential expression in many types of cancer. Moreover, LINC02298 is an important biomarker in a variety of tumors. This study established a novel ERLs signature, which successfully predicted the prognosis of OS. The function of LINC02298 in OS was elucidated via in vitro experiments. Therefore, it offers new opportunities for predicting the clinical prognosis of OS and establishes the basis for targeted therapy in OS.

Abstract To investigate the status of dignity impairment symptoms in critically ill patients after ICU treatment and conduct a systematic analysis of its influencing factors, aiming to provide reference for clinical medical decision-making by healthcare professionals. A cross-sectional survey study. From April 15th to 21st, 2024, a cross-sectional survey was conducted in 40 tertiary Grade A comprehensive hospitals in 9 provinces, municipalities, and autonomous regions including Sichuan Province, Zhejiang Province, and Chongqing Municipality. Various critically ill patients who were admitted to ICU treatment were surveyed using a general information questionnaire and the Dignity Inventory. A total of 346 questionnaires were collected in this survey, with 333 valid questionnaires and an effective response rate of 96%. The incidence rate of dignity impairment symptoms in critically ill patients after ICU treatment was 39%. Multifactor logistic regression analysis showed that age [OR = 1.124, 95%CI=(1.067–1.184)], frequency of visits [OR = 1.875, 95%CI=(1.075–3.269)], length of ICU stay [OR = 1.352, 95%CI=(1.108–1.649)], and tracheotomy upon discharge [OR = 2.269, 95%CI=(1.273–4.044)] were risk factors for dignity impairment symptoms in critically ill patients after ICU treatment. Number of children [OR = 0.247, 95%CI=(0.106–0.576)] was a protective factor for dignity impairment symptoms in critically ill patients after ICU treatment. Although the incidence of dignity impairment symptoms in critically ill patients after ICU treatment is relatively low, the psychological trauma it causes cannot be ignored. Healthcare professionals must actively establish and improve its prevention and management system.

Abstract This study aims to present age-stratified prevalence of women with lower urinary tract symptoms (LUTS) but without cystocele and predict detrusor underactivity (DU) or bladder outlet obstruction (BOO). Between 2005 and 2020, we reviewed women who visited the medical center with LUTS but without cystocele. Positive voiding dysfunction (VD) symptoms were defined as any one or more of the positive descriptions of weak urinary stream, intermittency, strain to urination, and sensation of not emptying. A total of 1,886 women were included in this study. 189 (10.0%) women were diagnosed with DU, and 77 (4.1%) women had BOO. Multivariate logistic regression analysis found that voided volume and VD symptoms were independent predictors for BOO. ROC curve analyses could predict BOO by voided volume ≤ 220 mL derived from uroflowmetry and the presence of VD symptoms with an area under a curve of 0.83. Age and voided volume could predict DU with an area under a curve of 0.82. We found a higher percentage of BOO in women with positive VD symptoms. A non-invasive uroflowmetry with voided volume (≤ 220 mL) and the presence of VD symptoms can predict BOO. DU could be predicted by age and voided volume.

Abstract Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder and metabolic abnormality disease that mainly affects women of reproductive age. LINC00173, a novel long noncoding RNA (lncRNA), has emerged as an important factor in the development of PCOS. However, the role of LINC00173 in PCOS development and its specific upstream and downstream mechanisms remain to be further clarified. Here, we found that LINC00173 was significantly upregulated in granulosa cells (GCs) of PCOS patients, and played a crucial role in promoting apoptosis of GCs. Mechanistically, we observed the activation of endoplasmic reticulum (ER) stress in the GCs of PCOS patients, and the ER stress sensor ATF4 could directly induce LINC00173 expression by binding to its promoter. LINC00173 further upregulated the expression of Harakiri (HRK) and subsequently inhibited downstream PI3K/AKT pathway. In conclusions, our study uncovered that ER stress-induced upregulation of LINC00173 leads to increased HRK expression and inhibition of the PI3K/AKT pathway, thereby promoting the progression of PCOS. These findings provide a new therapeutic strategy for the treatment of PCOS.

Abstract Some studies have identified influencing factors of COVID-19 illness in elderly, such as underlying diseases, but research on the effect of nutritional status is still lacking. This study retrospectively examined the influence of nutritional status on the outcome of elderly COVID-19 inpatients. A retrospective analysis of the clinical data of 4241 COVID-19 patients who were admitted to a third-class hospital of Nanchang between November 1, 2022 and January 31, 2023 was conducted. Nutritional status was assessed using the prognostic nutritional index (PNI) and controlling nutritional status score (CONUT). The influence of nutritional status on the outcome of COVID-19 patients was determined through multivariate adjustment analysis, restrictive cubic spline, and receiver operating characteristic curve (ROC). Compared with mild/no malnutrition, severe malnutrition substantially increased the critical outcome of COVID-19. A linear relationship was observed between the odds ratio (OR) and PNI and CONUT (P > 0.05). The area under the ROC curve indicated that PNI was the better predictor. The optimal cutoff value of PNI was 38.04 (95%CI: 0.797 ~ 0.836, AUC = 0.817), with a sensitivity of 70.7% and a specificity of 79.6%. The critical illness of elderly COVID-19 patients shows a linear relationship with malnutrition at admission. The use of PNI to assess the prognosis of COVID-19 eldeely patients is reliable, highlighting the importance for doctors to closely pay attention to the nutritional status of COVID-19 patients. Focusing on nutritional status in clinical practice can effectively reduce the critical illness of elderly COVID-19 patients.

Abstract Thyroid hormones (THs) may affect chronic thyrotoxic myopathy (CTM). The relationship between TH sensitivity and CTM is inconsistent. We aimed to investigate the associations between TH sensitivity and the risk of CTM and to screen potential CTMs with strength and function tests. A total of 162 Chinese patients (36.58% men) with Graves’ disease were enrolled and divided into CTM and non-CTM groups. TH and sensitivity indices were measured. Muscle power and function were assessed by grip, upper-limb fatigue (ULFT), lower-limb fatigue (LLFT), and squat-up (SUT) tests, and walking pace. Association between sensitivity to TH indices and the risk of developing CTM was assessed via multivariate logistic regression. The diagnostic effectiveness of muscle power and function for predicting CTM was evaluated via receiver operating characteristic (ROC) curves. Thyroid feedback quantile-based index FT3 (TFQIFT3) and the parametric TFQIFT3 (PTFQIFT3), TFQIFT4, and PTFQIFT4 were positively associated with CTM risk by using inverse probability of treatment weighting multivariate logistic regression. For each 1-SD increase in TFQIFT3 and PTFQIFT3, TFQIFT4 and PTFQIFT4, the odds ratios for CTM were 1.67 (95% CI = 1.17–2.48) ,1.64 (95% CI = 1.51–2.93), 1.60 (95%CI = 1.12–2.32), 1.58 (95%CI = 1.11–2.30), respectively. LLFT and SUT best predicted male/female CTM, respectively (AUC = 0.89/0.85). In Graves’ disease patients, TH sensitivity is associated with CTM development, which can be predicted by SUT and LLFT results.

Abstract Antibody-dependent enhancement (ADE) is a potential concern for the development of Zika virus (ZIKV) vaccines. Cross-reactive but poorly neutralizing antibodies, usually targeting viral pre-membrane or envelope (E) proteins, can potentially enhance dengue virus (DENV) infection. Although E domain III (EDIII) contains ZIKV-specific epitopes, its immunogenicity is poor. Here, we show that dimeric EDIII, fused to human IgG1 Fc fragment (EDIII-Fc) and encoded by circular RNA (circRNA), induces better germinal center reactions and higher neutralizing antibodies compared to circRNAs encoding monomeric or trimeric EDIII. Two doses of circRNAs encoding EDIII-Fc and ZIKV nonstructural protein NS1, another protective antigen, prevent lethal ZIKV infection in neonates born to immunized C57BL/6 mice and in interferon-α/β receptor knockout adult C57BL/6 mice. Importantly, a single-dose optimized circRNA vaccine with improved antigen expression confers potent and durable protection without inducing obvious DENV ADE in mice, laying the groundwork for developing flavivirus vaccines based on circRNAs encoding EDIII-Fc and NS1.

Abstract Water electro-oxidation to form H2O2 is an important way to produce H2O2 which is widely applied in industry. However, its mechanism is under debate and HO(ads), hydroxyl group adsorbed onto the surface of the electrode, is regarded as an important intermediate. Herein, we study the mechanism of water oxidation to H2O2 at Pt electrode using in-situ Raman spectroscopy and differential electrochemical mass spectroscopy and find peroxide bond mainly originated from the coupling of two CO3 2- via a C2O6 2- intermediate. By quantifying the 18O isotope in the product, we find that 93% of H2O2 was formed via the CO3 2- coupling route and 7% of H2O2 is from OH(ads)-CO3 •− route. The OH(ads)-OH(ads) coupling route has a negligible contribution. The comparison of various electrodes shows that the strong adsorption of CO3(ads) at the electrode surface is essential. Combining with a commercial cathode catalyst to produce H2O2 during oxygen reduction, we assemble a flow cell in which the cathode and anode simultaneously produce H2O2. It shows a Faradaic efficiency of 150% of H2O2 at 1 A cm−2 with a cell voltage of 2.3 V.

Abstract Utilizing ultrafast light-matter interaction to manipulate electronic states of quantum materials is an emerging area of research in condensed matter physics. It has significant implications for the development of future ultrafast electronic devices. However, the ability to induce long-lasting metastable electronic states in a fully reversible manner is a long-standing challenge. Here, by using ultrafast laser excitations, we demonstrate the capability to manipulate the electronic polar states in the charge-density-wave material EuTe4 in a non-volatile manner. The process is completely reversible and is achieved at room temperature with an all-optical approach. Each induced non-volatile state brings about modifications to the electrical resistance and second harmonic generation intensity. The results point to layer-specific phase inversion dynamics by which photoexcitation mediates the stacking polar order of the system. Our findings extend the scope of non-volatile all-optical control of electronic states to ambient conditions, and highlight a distinct role of layer-dependent phase manipulation in quasi-two-dimensional systems with inherent sublayer stacking orders.

Abstract While high-entropy alloy (HEA) catalysts seem to have the potential to break linear scaling relationships (LSRs) due to their structural complexity, the weighted averaging of properties among multiple principal components actually makes it challenging to diverge from the symmetry dependencies imposed by the LSRs. Herein, we develop a ‘surface entropy reduction’ method to induce the exsolution of a component with weak affinity for others, resulting in the formation of few-atom-layer metal (FL-M) on the surface of HEAs. These exsolved FL-M surpass the confines of the original configurational space of conventional HEAs, and collaborate with the HEA substrate, serving as geometrically separated active sites for multiple intermediates in a complex reaction. This FL-M-covered HEA shows an outstanding performance for electrocatalytic reduction of nitrate to ammonia (NH3) with a Faradaic efficiency of 92.7%, an NH3 yield rate of 2.45 mmol h–1 mgcat. –1, and high long-term stability (>200 h). Our work achieves the precise manipulation of atomic arrangement, thereby expanding both the chemical space occupied by known HEA catalysts and their potential application scenarios.

Abstract B cells play a key role in humoral immune responses by producing antibodies. Although there are numerous research on memory B cells definition markers and cytokines on B cell development, different studies have yielded contradictory conclusions due to species studied, the different cells and stimulating agents used. In the current study, we conducted a detailed characterization of B cells in human CBMCs, PBMCs and tonsil, including expression of Igs, activation and memory markers. Furthermore, we found that considerable amounts of IgA and IgG were expressed by CD27− B cells. These “Atypical” memory B cells corresponded to approximately 50% of IgG+ and IgA+B cells in blood, this proportion even reached 90% in tonsil. In addition, we investigated the effect of IL-21 and TGF-β1 on the membrane-bound form and secreted form of Igs using PBMCs and purified blood B cells. There were actual differences between the effect of cytokines on Igs secretion and surface expression. Our study will be helpful to advance the knowledge and understanding of humoral memory.

Abstract This research delves into the dynamic behavior of acoustic levitation of the particle chain in a nonlinear standing wave field. Experimental acoustic levitation control tests reveal bifurcation and jump phenomena during dynamic adjustments to resonant cavity height. Employing the 10-particle chain experiments and the COMSOL simulation models, the Sine-Gordon 2D vibration model is established to study the dynamic deformation process of the particle chain. The study uncovers the nonlinear interaction of particle lateral vibrations, horizontal acoustic radiation force, and conical wave fields that generate the jumping standing wave field. Notably, the fourth particle acts as a prominent jumping critical point in the secondary standing wave field, facilitating the derivation of the particle chain’s nonlinear levitation dynamics. This discovery provides us with a new method to regulate the particle chain system.

Abstract Transposable elements (TEs) are crucial for genetic diversity and gene regulation. Current single-cell quantification methods often align multi-mapping reads to either ‘best-mapped’ or ‘random-mapped’ locations and categorize them at the subfamily levels, overlooking the biological necessity for accurate, locus-specific TE quantification. Moreover, these existing methods are primarily designed for and focused on transcriptomics data, which restricts their adaptability to single-cell data of other modalities. To address these challenges, here we introduce MATES, a deep-learning approach that accurately allocates multi-mapping reads to specific loci of TEs, utilizing context from adjacent read alignments flanking the TE locus. When applied to diverse single-cell omics datasets, MATES shows improved performance over existing methods, enhancing the accuracy of TE quantification and aiding in the identification of marker TEs for identified cell populations. This development facilitates the exploration of single-cell heterogeneity and gene regulation through the lens of TEs, offering an effective transposon quantification tool for the single-cell genomics community.

Abstract Liposarcoma (LPS) is the second most common kind of soft tissue sarcoma, and a heterogeneous malignant tumor derived from adipose tissue. Up to now, the prognostic value of BAG1 or BAG2 in LPS has not been defined yet. Expression profiling data of LPS patients were collected from TCGA and GEO database. Survival curves were plotted to verify the outcome differences of patients based on BAG1 or BAG2 expression. Univariate and multivariate Cox regression models were used to analyze the prognostic ability of BAG1 or BAG2. Chaperone’s regulators BAG1 and BAG2 were identified as prognostic biomarkers for LPS patients, which exhibited distinct expression patterns and survival outcome prediction performances. Patients with high BAG2 expression and/or low BAG1 expression had worse prognosis. Enrichment analysis showed that BAG1 was involved in negative regulation of TGF-β signaling. Low expression of BAG1 was associated with high abundance of regulatory T cells (Tregs). The 2-gene signature model further confirmed the improved risk assessment performance of BAG1 and BAG2: high risk patients displayed poor prognosis. BAG1 and BAG2 are supposed to be potential prognostic biomarkers for LPS and have impacts on liposarcomagenesis and immune infiltration in distinctive manners, which may function as potential therapy targets (BAG1 agonists/BAG2 inhibitors) for LPS.

Abstract Ni-based catalysts are highly reactive for dry reforming of methane (DRM) but they are prone to rapid deactivation due to sintering and/or coking. In this study, we present a straightforward approach for anchoring dispersed Ni sites with strengthened metal-support interactions, which leads to Ni active sites embedded in dealuminated Beta zeolite with superior stability and rates for DRM. The process involves solid-state grinding of dealuminated Beta zeolites and nickel nitrate, followed by calcination under finely controlled gas flow conditions. By combining in situ X-ray absorption spectroscopy and ab initio simulations, it is elucidated that the efficient removal of byproducts during catalyst synthesis is conducted to strengthen Ni–Si interactions that suppress coking and sintering after 100 h of time-on-stream. Transient isotopic kinetic experiments shed light on the differences in intrinsic turnover frequency of Ni species and explain performance trends. This work constructs a fundamental understanding regarding the implication of facile synthesis protocols on metal-support interaction in zeolite-supported Ni sites, and it lays the needed foundations on how these interactions can be tuned for outstanding DRM performance.

Abstract Rapid glucose supply is crucial for animal survival during stress response. How the timescale of stress-induced glucose release precisely controlled by hypothalamic corticotropin-releasing hormone (CRH) neurons remains unclear. Here, we show that stress-induced hyperglycemia can be divided into at least two stages in male mice: the first fast stage is mediated by hypothalamus (paraventricular to ventromedial hypothalamus)-sympathetic (raphe pallidus nucleus to intermediolateral nucleus)-liver (HSL) axis activity; the second delayed stage is mediated by adrenal activity. Blocking the activity of HSL axis impairs predatory evoked flight responses, indicating that the HSL pathway activity is necessary for stress coping. We further reveal the intracellular signal cascade for CRH signal in the hypothalamus, which is mediated by GABAA receptor β3 subunit phosphorylation at S408/409, results in prevention of GABAA receptor membrane recruitment. Thus, we uncovered the precise timescale of glucose supply during stress which is mediated by adrenal independent HSL and adrenal dependent pathway respectively.

Abstract Seed size, a key determinant of rice yield, is regulated by brassinosteroid (BR); however, the BR pathway in rice has not been fully elucidated. Here, we report the cloning and characterization of the quantitative trait locus Rice Big Grain 1 (qRBG1) from single-segment substitution line Z499. Our data show that qRBG1 Z is an unselected rare promoter variation that reduces qRBG1 expression to increase cell number and size, resulting in larger grains, whereas qRBG1 overexpression causes smaller grains in recipient Nipponbare. We demonstrate that qRBG1 encodes a non-canonical BES1 (Bri1-EMS-Suppressor1)/BZR1(Brassinazole-Resistant1) family member, OsBZR5, that regulates grain size upon phosphorylation by OsGSK2 (GSK3-like Kinase2) and binding to D2 (DWARF2) and OFP1 (Ovate-Family-Protein1) promoters. qRBG1 interacts with OsBZR1 to synergistically repress D2, and to antagonistically mediate OFP1 for grain size. Our results reveal a regulatory network controlling grain size via OsGSK2–qRBG1–OsBZR1–D2–OFP1 module, providing a target for improving rice yield.

Abstract M1 macrophages induce protective immunity against infection, but also contribute to metabolic and inflammatory diseases. Here we show that the E3 ubiquitin ligase, MDM2, promotes the glycolytic and inflammatory activities of M1 macrophage by increasing the production of IL-1β, MCP-1 and nitric oxide (NO). Mechanistically, MDM2 triggers the ubiquitination and degradation of E3 ligase, SPSB2, to stabilize iNOS and increases production of NO, which s-nitrosylates and activates HIF-1α for triggering the glycolytic and pro-inflammatory programs in M1 macrophages. Myeloid-specific haplodeletion of MDM2 in mice not only blunts LPS-induced endotoxemia and NO production, but also alleviates obesity-induced adipose tissue-resident macrophage inflammation. By contrast, MDM2 haplodeletion induces higher mortality, tissue damage and bacterial burden, and also suppresses M1 macrophage response, in the cecal ligation and puncture-induced sepsis mouse model. Our findings thus identify MDM2 as an activator of glycolytic and inflammatory responses in M1 macrophages by connecting the iNOS-NO and HIF-1α pathways.

Abstract Break-induced replication (BIR) is mutagenic, and thus its use requires tight regulation, yet the underlying mechanisms remain elusive. Here we uncover an important role of 53BP1 in suppressing BIR after end resection at double strand breaks (DSBs), distinct from its end protection activity, providing insight into the mechanisms governing BIR regulation and DSB repair pathway selection. We demonstrate that loss of 53BP1 induces BIR-like hyperrecombination, in a manner dependent on Polα-primase-mediated end fill-in DNA synthesis on single-stranded DNA (ssDNA) overhangs at DSBs, leading to PCNA ubiquitination and PIF1 recruitment to activate BIR. On broken replication forks, where BIR is required for repairing single-ended DSBs (seDSBs), SMARCAD1 displaces 53BP1 to facilitate the localization of ubiquitinated PCNA and PIF1 to DSBs for BIR activation. Hyper BIR associated with 53BP1 deficiency manifests template switching and large deletions, underscoring another aspect of 53BP1 in suppressing genome instability. The synthetic lethal interaction between the 53BP1 and BIR pathways provides opportunities for targeted cancer treatment.