Hypoxia-preconditioned bone marrow-derived mesenchymal stem cells protect neurons from cardiac arrest-induced pyroptosis.

JOURNAL/nrgr/04.03/01300535-202504000-00027/figure1/v/2024-07-06T104127Z/r/image-tiff Cardiac arrest can lead to severe neurological impairment as a result of inflammation, mitochondrial dysfunction, and post-cardiopulmonary resuscitation neurological damage. Hypoxic preconditioning has been shown to improve migration and survival of bone marrow-derived mesenchymal stem cells and reduce pyroptosis after cardiac arrest, but the specific mechanisms by which hypoxia-preconditioned bone marrow-derived mesenchymal stem cells protect against brain injury after cardiac arrest are unknown. To this end, we established an in vitro co-culture model of bone marrow-derived mesenchymal stem cells and oxygen-glucose deprived primary neurons and found that hypoxic preconditioning enhanced the protective effect of bone marrow stromal stem cells against neuronal pyroptosis, possibly through inhibition of the MAPK and nuclear factor κB pathways. Subsequently, we transplanted hypoxia-preconditioned bone marrow-derived mesenchymal stem cells into the lateral ventricle after the return of spontaneous circulation in an 8-minute cardiac arrest rat model induced by asphyxia. The results showed that hypoxia-preconditioned bone marrow-derived mesenchymal stem cells significantly reduced cardiac arrest-induced neuronal pyroptosis, oxidative stress, and mitochondrial damage, whereas knockdown of the liver isoform of phosphofructokinase in bone marrow-derived mesenchymal stem cells inhibited these effects. To conclude, hypoxia-preconditioned bone marrow-derived mesenchymal stem cells offer a promising therapeutic approach for neuronal injury following cardiac arrest, and their beneficial effects are potentially associated with increased expression of the liver isoform of phosphofructokinase following hypoxic preconditioning.

Photothermal switch by gallic acid-calcium grafts synthesized by coordination chemistry for sequential treatment of bone tumor and regeneration.

The residual bone tumor and defects which is caused by surgical therapy of bone tumor is a major and important problem in clinicals. And the sequential treatment for irradiating residual tumor and repairing bone defects has wildly prospects. In this study, we developed a general modification strategy by gallic acid (GA)-assisted coordination chemistry to prepare black calcium-based materials, which combines the sequential photothermal therapy of bone tumor and bone defects. The GA modification endows the materials remarkable photothermal properties. Under the near-infrared (NIR) irradiation with different power densities, the black GA-modified bone matrix (GBM) did not merely display an excellent performance in eliminating bone tumor with high temperature, but showed a facile effect of the mild-heat stimulation to accelerate bone regeneration. GBM can efficiently regulate the microenvironments of bone regeneration in a spatial-temporal manner, including inflammation/immune response, vascularization and osteogenic differentiation. Meanwhile, the integrin/PI3K/Akt signaling pathway of bone marrow mesenchymal stem cells (BMSCs) was revealed to be involved in the effect of osteogenesis induced by the mild-heat stimulation. The outcome of this study not only provides a serial of new multifunctional biomaterials, but also demonstrates a general strategy for designing novel blacked calcium-based biomaterials with great potential for clinical use.

Supporting driver performance in closely spaced tunnel-interchange structure: Traffic control devices and effects on driving behavior.

OBJECTIVES: With the rapid development of expressways in the mountainous regions of southwestern China, closely spaced tunnel-interchange structures have inevitably emerged due to topographical constraints and environmental limitations. Given the unfavorable road geometry and rapid cross-section transitions, drivers face significant safety concerns. This study aims to investigate drivers' safety performance at closely spaced tunnel-interchange sections and determine how safety risks can be mitigated through improved traffic control devices design. METHODS: Thirty-nine participants conducted an experimental study in a fixed-base simulator. The test scenario was modeled on the Xingyan Freeway-S3801 and accurately reproduced in the simulator. For each safety performance metric, the driving simulator experiments yielded a dataset with 780 observations. To address the idiosyncratic variation due to individual driver differences, a series of linear mixed effects models (LMM) were developed to analyze drivers' behavior responses. RESULTS: In closely spaced tunnel-interchange sections, a general impairment of both longitudinal and lateral performance was observed. This study identified potential critical impact variables in traffic control device systems. According to the LMM results: (a) Removing the 0.5 km interchange ramp exit advance guide sign located in the tunnel exit area reduces dangerous behavior in the corresponding impact area. (b) Replacing the 0.5 km interchange ramp exit advance guide sign with arrow pavement markers as an information source supports improved driver performance, promoting driver safety. (c) Adding tunnel exit distance signs within tunnels is recommended to enhance situation awareness for drivers. CONCLUSIONS: This study addresses the scientific issues related to traffic control devices setup for closely spaced tunnel-interchange sections, focusing on identifying potential critical impact variables. The findings provide guidance on the design of traffic control devices for such sections and support revisions to national engineering standards.

Observation of multiple topological bound states in the continuum in the photonic bilayer trimer lattice.

A topological bound state in the continuum (TBIC) is a novel topological phase that has attracted significant attention. Different from conventional topological insulators (TIs), where boundary states reside within gaps, TBICs can support unconventional boundary states that remain isolated from the surrounding bulk states. In this work, we experimentally demonstrate multiple TBICs in photonic bilayer trimer lattices using femtosecond laser writing technology. By modulating the interlayer coupling between two trimer chains, we observe the emergence of two distinct types of TBICs. Moreover, we experimentally achieve the coexistence of in-gap topological states and TBICs and demonstrate the transformation between them. Our work unveils new insights into the flexible construction of TBICs, and this method can be easily applied to other one-dimensional topological structures, offering promising avenues for further research.

Proteomic biomarkers of long-term lung function decline in textile workers: a 35-year longitudinal study.

BACKGROUND: Occupational exposures contribute significantly to obstructive lung disease among textile workers. However, biomarkers associated with such declines are not available. OBJECTIVES: We conducted a large-scale proteomic study to explore protein biomarkers potentially associated with long-term lung function decline. METHODS: Shanghai Textile Workers Cohort was established in 1981 with 35 years of follow-up, assessing textile workers' lung functions every five years. Quantitative serum proteomics was performed on all 453 workers at 2016 survey. We employed four distinct models to examine the association between forced expiratory volume in one second (FEV1) and proteins, and consolidated the findings using an aggregated Cauchy association test. Furthermore, proteomic data of UK Biobank (UKB) was used to explore the associations of potential protein markers and decline of FEV1, and the interactions of these proteins were examined through STRING database. Associations were also externally validated using two-sample Mendelian randomizations (MR). RESULTS: 15 of 907 analyzed proteins displayed potential associations with long-term FEV1 decline, including two hemoglobin subunits: hemoglobin subunit beta (HBB, FDR-qACAT = 0.040), alpha globin chain (HBA2, FDR-qACAT = 0.045), and four immunoglobulin subunits: immunoglobulin kappa variable 3-7 (IGKV3-7, FDR-qACAT = 0.003), immunoglobulin heavy chain variable region (IgH, FDR-qACAT = 0.011). Five proteins were significantly associated with the rate of decline of FEV1 in UKB, in which RAB6A, LRRN1, and BSG were also found to be associated with proteins identified in Shanghai Textile Workers Cohort using STRING database. MR indicated bidirectional associations between HBB and FEV1 (P < 0.05), while different immunoglobulin subunits exhibited varying associations with FEV1. IMPACT STATEMENT: We performed a large-scale proteomic study of the longest-follow-up pulmonary function cohort of textile workers to date. We discovered multiple novel proteins associated with long-term decline of FEV1 that have potential for identifying new biomarkers associated with long-term lung function decline among occupational populations, and may identify individuals at risk, as well as potential pharmaceutical targets for early intervention.

Application value of ultrasonic contrast imaging and ultrasonic parameters in post-transplant renal surgery.

Objective: Utilize VUEBOX quantitative analysis software to perform quantitative analysis dynamic ultrasound contrast images of post-transplant renal patients were assessed quantitatively five parameters of ultrasonic contrast and two-dimensional ultrasound are examined to explore their six value in Diagnosing Renal Graft Dysfunction. Methods: A retrospective analysis was conducted on 73 post-transplant renal patients who underwent ultrasound contrast examinations at Yiyang Central Hospital from July 2022 to December 2023, They were diagnosed clinically and pathologically. Based on pathological and clinical diagnostic results, the patients were divided into three groups: 47 cases in the stable renal function group, 18 cases in the acute rejection (AR) group, and 8 cases in the delayed graft function (DGF) group. All patients underwent routine ultrasound and ultrasound contrast examinations post-transplantation. By comprehensively assessing renal function test results, clinical course, and pathological findings, differences in ultrasonic contrast quantitative parameters were analyzed. Additionally, ROC curves were constructed to evaluate the diagnostic efficacy of ultrasound contrast in discriminating between transplant renal rejection reactions and delayed renal function recovery. Results: Statistically significant differences in characteristics, such as renal segmental artery resistance index, were observed among the stable renal function group, AR group, and DGF group (all P < 0.05), while peak systolic velocity showed no statistical significance (P > 0.05). Differences in cortical time to peak (TTP), medullary time to peak(TTP), main renal artery rise time (RT), main renal artery(TTP), and main renal artery fall time (FT) were statistically significant among the stable renal function group, AR group, and DGF group (P < 0.05). ROC curve analysis demonstrated that the accuracy of quantitative parameters for the DGF group and AR group was as follows: Renal artery TTP = Renal artery RT > Renal artery FT > Medulla TTP > Cortex TTP (with respective area under the curve values of 0.828, 0.828, 0.758, 0.742, 0.719). Among these, Renal artery TTP and Renal artery RT exhibited larger AUC values, with sensitivities of 87.5% each and specificities of 81.2 and 87.5%, respectively. Conclusion: There are discernible differences in VUEBOX quantitative parameters between post-transplant AR and DGF cases, thereby providing imaging references for diagnosing of acute rejection and functional impairment following renal transplantation.

Construction of a thermoresponsive molecularly imprinted biomimetic hydrogel-based virus sensor and non-invasive cyclable detection of EV71.

A thermoresponsive molecularly imprinted hydrogel sensor was constructed for the specific selective recognition of enterovirus 71 (EV71). Due to the introduction of the thermosensitive monomer N-isopropylacrylamide (NIPAM), when the imprinted hydrogel is incubated with the virus at 37℃, the surface specific imprinting cavity will specifically recognize and capture the target virus EV71. When the temperature rises to 45℃, the combined EV71 is rapidly released due to changes in the shape and function of the imprinted sites. The MIP hydrogel-based viral sensor developed recognized, captured, and released the target virus in a non-invasive way. The imprinting factor of the target virus was 5.2, suggesting high selectivity, and the detection limit was 7.1 fM, suggesting high sensitivity. Detection was rapid, as adsorption equilibrium was achieved within 30 min. This method provides a new sustainable avenue for the simple and rapid detection of viruses.

CDT1, transcriptionally regulated by E2F2, promotes lung adenocarcinoma progression.

CDT1, a gene that shows excessive expression in various malignancies, functions as a pivotal regulator of replication licensing. In this study, we observed a positive correlation in expression between CDT1 and E2F2 among patients with lung adenocarcinoma (LUAD). Our findings substantiated that E2F2 directly interacted with the promoter region of CDT1, as confirmed by ChIP-qPCR assays, and depletion of E2F2 resulted in a downregulation of CDT1 expression in LUAD cell lines by gene interference technology. Furthermore, we identified an upregulation of CDT1 mRNA level in Chinese LUAD samples. Notably, in the loss-of-function assays, depletion of CDT1 in LUAD cell lines inhibited cell proliferation, migration, and invasion. Concurrently, it promoted cell apoptosis and induced G0/G1 phase arrest using MTT, flow cytometry, and Transwell assays, reinforcing its role as an oncogene.Furthermore, enhanced tumor ablation was determined in a CDT1-downregulated LUAD tumor-bearing nude mouse model. Collectively, our results strongly suggest that E2F2 positively regulates CDT1 expression and actively participates in the progression of lung adenocarcinoma, thereby providing valuable insights into identifying novel therapeutic targets for LUAD treatment.

Synthesis and Spectroscopic Study of a Homogenous Bimetallic Os(II) Complex as a New Gastric Cancer Photosensitizer.

A homogenous dinuclear Os(II) complex bisOs was synthesized and fully characterized. The electrochemical cyclic voltammetry study, and density functional theory (DFT) and time-dependent DFT (TD-DFT) calculations were performed to investigate the electronic property. bisOs showed an obvious interaction with lipase and BSA, and can generate singlet oxygen under blue and red LED light irradiation, with a singlet oxygen quantum yield (ФΔ) of 0.36 in comparison to that of [Ru(bpy)3]Cl2 in acetonitrile. bisOs exhibited moderate to great photocytotoxicity against HGC-27 human gastric cancer cells under blue LED light irradiation, giving the IC50 value as low as 1.83 µM (PI value is 9.7), while was almost non-cytotoxic in the dark. The cellular singlet oxygen detection in HGC-27 cancer cells exhibited a concentration-dependent manner, and cell uptake of bisOs in A549 cells was as high as 120 ng/106 cells, subcellular colocalization study indicated that bisOs was not accumulated in nucleus, and less likely to target mitochondria. This work provides a new example of dinuclear osmium complex as potential photosensitizer candidate for gastric treatment.

On-site SERS analysis and intelligent multi-identification of fentanyl class substances by deep machine learning.

As the types of fentanyl class substances continue to grow, a universal SERS sensor is essential for the application of discriminant detection of fentanyl substances. A new nanomaterial SERS sensor-Ag@Au NPs-paper was developed. The SERS sensitivity and stability of Ag@Au NPs-paper were investigated by using R6G molecule, and the results showed that Ag@Au NPs-paper has excellent performance. In combination with visual analysis and machine learning methods, Ag@Au NPs-paper has been successfully applied to the analysis of fentanyl class substances and the component identification of binary fentanyl mixtures, and thus it can be effectively used in food safety, environmental toxicants and other fields.

Cardiorespiratory fitness, independent of APOE genotype, is associated with better neurocognitive function in older adults: An ERP study.

This study assessed the association between cardiorespiratory fitness and carriage of the apolipoprotein-E ε4 allele (APOE ε4) and cognitive function using behavioral and neuroelectric measures obtained from cognitively normal older adults. A total of 159 adults aged 50-70 years were categorized into four groups based on cardiorespiratory fitness (i.e., higher vs. lower fitness) and APOE genotype (i.e., APOE ε4 carrier vs. non-carrier). Neurocognitive functions were indexed using response time and accuracy measures from the Stroop Test and averaged mean P3 amplitudes of event-related potentials obtained during task performance. A significant main effect of cardiorespiratory fitness (p = .02) and Stroop congruency (p < .001), but not APOE genotype status, with shorter response times for the higher fitness group than for the lower fitness group and for the congruent condition relative to the incongruent condition, were observed. Similar findings were also revealed, with larger averaged mean P3 amplitudes for the higher fitness group than those in the lower fitness group, and in the congruent condition than in the incongruent condition. These findings suggest that higher cardiorespiratory fitness is linked to better neurocognitive function, and the positive association is evident regardless of APOE ε4 status and the cognitive domain assessed in cognitively normal older adults.

[Mechanism of ganoderic acid X in treating hepatoblastoma based on proteomics].

This research explored the mechanism of ganoderic acid X(GAX) on human hepatocellular carcinoma cell models(HepG2, HuH6) and nonobese diabetic-severe combined immune deficient(NOD-SCID) mouse subcutaneous tumor models using proteomics, aiming to provide a basis for the clinical application of GAX. CCK-8 assay was employed to evaluate the effect of GAX on the viability of HepG2 and HuH6 cells. EdU assay was used to assess the effect of GAX on cell proliferation. Scratch assay was used to examine the effect of GAX on cell migration ability. Hoechst 33258 staining was used to investigate the effect of GAX on cell apoptosis. Moreover, a NOD-SCID mouse subcutaneous tumor model was established to analyze the tumor volume and weight in control group and GAX low-, medium-, and high-dose groups(5, 10, and 20 mg·kg~(-1)). HE staining was conducted to evaluate the drug toxicity of GAX. Additionally, HepG2 cells in the control group and the GAX high-dose group were subjected to label-free proteomics analysis to identify differential proteins and enrich relevant signaling pathways. CYTO-ID® staining was performed to detect autophagy, and Western blot was conducted to measure the expression levels of relevant proteins. In vitro results demonstrated that GAX dose-depen-dently inhibited proliferation, migration, and induced apoptosis in HepG2 and HuH6 cells. In vivo studies showed that GAX significantly inhibited tumor volume and weight without causing significant damage to major organs(heart, liver, spleen, lung, and kidney) in mice. Label-free proteomics analysis revealed that GAX participated in multiple signaling pathways during the treatment of hepatocellular carcinoma, with a high enrichment in the autophagy pathway. CYTO-ID® staining and Western blot results showed that GAX induced autophagy, upregulated the expression of Beclin-1, ATG5, and LC3-Ⅱ proteins, and downregulated the expression of p62 protein. This study suggests that GAX inhibits the proliferation, migration, and induces apoptosis of hepatocellular carcinoma cells by inducing autophagy, thereby significantly inhibiting tumor growth. GAX represents a promising adjuvant therapy for cancer treatment.

A splice-switch oligonucleotide loaded self-cleavable DNA nanogel.

A self-cleavable DNA nanogel loaded with splice-switch oligonucleotide (SSO) has been developed. Under acidic conditions (pH 5.0), cleavage of the acid-labile chemical linker and generation of the i-motif structure led to the disintegration of the DNA nanogel and efficient release of SSO in its unaltered native state.

CYP2C19 genotype and sodium channel blockers in lacosamide-treated children with epilepsy: two major determinants of trough lacosamide concentration or clinical response.

Background: The widespread clinical use of lacosamide (LCM) has revealed significant individual differences in clinical response, with various reported influencing factors. However, it remains unclear how genetic factors related to the disposition and clinical response of LCM, as well as drug-drug interactions (DDIs), exert their influence on pediatric patients with epilepsy. Objectives: To evaluate the impact of genetic variations and DDIs on plasma LCM concentrations and clinical response. Design: Patients with epilepsy treated with LCM from June 2021 to March 2023 in the Children's Hospital of Nanjing Medical University were included in the analysis. Methods: The demographic information and laboratory examination data were obtained from the hospital information system. For the pharmacogenetic study, the left-over blood specimens, collected for routine plasma LCM concentration monitoring, were used to perform genotyping analysis for the selected 26 single nucleotide polymorphisms from 14 genes. The trough concentration/daily dose (C 0/D) ratio and efficacy outcomes were compared. Results: Patients achieved 90.1% and 68.9% responder rates in LCM mono- and add-on therapy, respectively. The genetic variant in the CYP2C19 *2 (rs4244285) was associated with a better responsive treatment outcome (odds ratio: 1.82; 95% confidence interval: 1.05-3.15; p = 0.031). In monotherapy, 36% of patients were CYP2C19 normal metabolizers (NMs), 49% were intermediate metabolizers (IMs), and 15% were poor metabolizers (PMs) carrying CYP2C19 *2 or *3. Of note, the C 0/D ratios of IMs and PMs were 9.1% and 39.6% higher than those of NMs, respectively. Similar results were in the add-on therapy group, and we also observed a substantial decrease in the C 0/D ratio when patients were concomitant with sodium channel blockers (SCBs). Conclusion: This study was the first to confirm that CYP2C19 *2 or *3 variants impact the disposition and treatment response of LCM in children with epilepsy. Moreover, concomitant with SCBs, particularly oxcarbazepine, also decreased plasma LCM concentration.

CYP2C19 genotype and sodium channel blockers in lacosamide-treated children with epilepsy: two major determinants of plasma lacosamide concentration or treatment efficacy This study examined the impact of genetic factors and drug combinations on the effectiveness and plasma concentrations of lacosamide, an antiseizure medication, in patients under 18. Analyzing blood samples from 316 patients at the Children's Hospital of Nanjing Medical University, researchers discovered that genetic variations in the CYP2C19 (i.e. *2 and *3), along with metabolic capacity, and co-medication with sodium channel blockers, all influence plasma lacosamide concentration. Understanding these genetic influences could inform personalized dosing strategies, improving the medication's management for pediatric epilepsy patients.

A bulge uridine in the HIF2a IRE allows IRP1 but not IRP2 to selectively regulate HIF2a expression and ensuing EPO levels.

Iron regulatory proteins (IRP1 and IRP2) play a pivotal role in maintaining cellular iron homeostasis by binding to iron-responsive elements (IREs) of target mRNAs and regulating the expression of these iron-related genes. Mice and humans that lack functional IRP1 develop erythrocytosis due to erythropoietin overproduction, whereas those that lack IRP2 develop microcytic anemia believed to result from iron deficiency of erythroblasts. Here, we discovered that IRP2 deficiency reduced the expression of hypoxia inducible factor 2 alpha (HIF2a) and its transcriptional target, erythropoietin (EPO), thereby compromising the stress erythropoiesis response to generate RBCs upon anemia. The distinct consequences of IRP2 and IRP1 on EPO result from the higher binding affinity of the HIF2a IRE for IRP1 compared to IRP2. This difference in binding affinity arises from a bulge uridine in the upper stem of HIF2a IRE that impairs the ability of IRP2 to bind the IRE. These results reveal that IRP1 and IRP2 play distinct roles in erythropoiesis and unveil an unsuspected IRE binding preference that contributes to the divergent phenotypes observed in IRP1 and IRP2 deficient mammals.

A national-wide survey on clinical implementation of PGx testing into precision therapeutics for Chinese children: a long way before standard clinical practice.

BACKGROUND: Pharmacogenetics/pharmacogenomics (PGx) focuses on the genetic variation that causes the heterogeneity of pharmacokinetics and drug response among individuals and has the potential to predict individual efficacy and/or side effects. This study aims to investigate and understand the implementation of genetic testing for the personalized medication (GTPM) in children's hospitals in Mainland China. METHODS: A survey was conducted on 50 children's hospitals from 31 provinces, municipalities, and autonomous regions across Mainland China, and statistical analysis and recommendations were made. RESULTS: Questionnaire response was rate of 76.0% (38/50). Data from 15 hospitals conducting GTPM were included in this study, but only 6 hospitals had offered PGx tests for no less than five drug-related genes, and only 5 hospitals had covered more than ten drugs, which was a small scale overall. 20.0% of the laboratories did not conduct internal quality control, and 33.3% did not participate in inter-laboratory quality assessment. 46.7% of the practitioners did not receive external training. The primary goal for GTPM was to optimize drug dosage in the 15 hospitals, while the main challenge for GTPM was the implementation cost. CONCLUSION: Although GTPM in pediatrics has made major progress in Mainland China in recent years, there were still various problems in terms of software, hardware configuration, personnel allocation, business scale, quality control, and result interpretation. This requires joint efforts of health administration, medical insurance departments, researchers, and hospitals to promote and improve GTPM.

Genetically predicted frailty index and risk of chronic kidney disease.

Previous findings have reported the association between frailty and chronic kidney disease. However, the causality remains ambiguous. This study aimed to determine whether frailty index is causally associated with chronic kidney disease. We obtained the frailty genome-wide association study (GWAS) data and chronic kidney disease GWAS data from the FinnGen R5 (total n = 216,743; case = 3902, control = 212,841) as the exposure and outcome, respectively. A two-sample Mendelian randomization (MR) analysis was primarily conducted using the inverse-variance weighted (IVW), weighted median and MR-Egger regression analyses. Multivariable MR analysis (MVMR) was conducted for additional adjustment. In the two-sample Mendelian randomization analyses, a total of 14 single nucleotide polymorphisms (SNPs) were recognized as effective instrumental variables. The IVW method showed evidence to support a causal association between frailty index and chronic kidney disease (beta = 1.270; 95% CI 0.608 to 1.931; P < 0.001). MR-Egger revealed a causal association between frailty index and chronic kidney disease (beta = 3.612; 95% CI 0.805 to 6.419; P = 0.027). MR-Egger regression revealed that directional pleiotropy was unlikely to be biasing the result (intercept = - 0.053; P = 0.119). The weighted median approach and weighted mode method also demonstrated a causal association between frailty index and chronic kidney disease (beta = 1.148; 95% CI 0.278 to 2.019; P = 0.011; beta = 2.194; 95% CI 0.598 to 3.790; P = 0.018). Cochran's Q test and the funnel plot indicated no directional pleiotropy. MVMR analysis revealed that the causal association between frailty index and chronic kidney disease remained after adjusting for potential confounders, body-mass index, inflammatory bowel disease, waist-hip ratio, and C-reactive protein. Our study provides evidence of causal association between frailty and chronic kidney disease from genetic perspectives.

Effect of single blastocyst-stage versus single cleavage-stage embryo transfer on cumulative live births in women with good prognosis undergoing in vitro fertilization: Multicenter Randomized Controlled Trial.

In this multicenter, non-inferiority, randomized trial, we randomly assigned 992 women undergoing in-vitro fertilization (IVF) with a good prognosis (aged 20-40, ≥3 transferrable cleavage-stage embryos) to strategies of blastocyst-stage (n = 497) or cleavage-stage (n = 495) single embryo transfer. Primary outcome was cumulative live-birth rate after up to three transfers. Secondary outcomes were cumulative live-births after all embryo transfers within 1 year of randomization, pregnancy outcomes, obstetric-perinatal complications, and livebirths outcomes. Live-birth rates were 74.8% in blastocyst-stage group versus 66.3% in cleavage-stage group (relative risk 1.13, 95%CI:1.04-1.22; Pnon-inferiority < 0.001, Psuperiority = 0.003) (1-year cumulative live birth rates of 75.7% versus 68.9%). Blastocyst transfer increased the risk of spontaneous preterm birth (4.6% vs 2.0%; P = 0.02) and neonatal hospitalization >3 days. Among good prognosis women, a strategy of single blastocyst transfer increases cumulative live-birth rates over single cleavage-stage transfer. Blastocyst transfer resulted in higher preterm birth rates. This information should be used to counsel patients on their choice between cleavage-stage and blastocyst-stage transfer (NCT03152643, https://clinicaltrials.gov/study/NCT03152643 ).

Efficient Communication via Self-Supervised Information Aggregation for Online and Offline Multiagent Reinforcement Learning.

Utilizing messages from teammates can improve coordination in cooperative multiagent reinforcement learning (MARL). Previous works typically combine raw messages of teammates with local information as inputs for policy. However, neglecting message aggregation poses significant inefficiency for policy learning. Motivated by recent advances in representation learning, we argue that efficient message aggregation is essential for good coordination in cooperative MARL. In this article, we propose Multiagent communication via Self-supervised Information Aggregation (MASIA), where agents can aggregate the received messages into compact representations with high relevance to augment the local policy. Specifically, we design a permutation-invariant message encoder to generate common information-aggregated representation from messages and optimize it via reconstructing and shooting future information in a self-supervised manner. Hence, each agent would utilize the most relevant parts of the aggregated representation for decision-making by a novel message extraction mechanism. Furthermore, considering the potential of offline learning for real-world applications, we build offline benchmarks for multiagent communication, which is the first as we know. Empirical results demonstrate the superiority of our method in both online and offline settings. We also release the built offline benchmarks in this article as a testbed for communication ability validation to facilitate further future research in this direction.

The aroma transformation of Japanese sea bass (Lateolabrax japonicas) through endogenous enzyme incubation during the lag phase of attached microorganisms.

Endogenous enzymes play a crucial role in determining fish product aroma. However, the attached microorganisms can promote enzyme production, making it challenging to identify specific aromatic compounds resulting from endogenous enzymes. Thus, we investigated the aroma transformation of Japanese sea bass through enzymatic incubation by controlling attached microorganisms during the lag phase. Our results demonstrate that enzymatic incubation significantly enhances grassy and sweet notes while reducing fishy odors. These changes in aroma are associated with increased levels of 10 volatile compounds and decreased levels of 3 volatile compounds. Among them, previous studies have reported enzyme reaction pathways for octanal, 1-nonanal, vanillin, indole, linalool, geraniol, citral, and 6-methyl-5-hepten-2-one; however, the enzymatic reaction pathways for germacrene D, beta-caryophyllene, pristane, 1-tetradecene and trans-beta-ocimene remain unclear. These findings provide novel insights for further study to elucidate the impact of endogenous enzymes on fish product aromas.