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Accurate prediction of RNA three-dimensional (3D) structures remains an unsolved challenge. Determining RNA 3D structures is crucial for understanding their functions and informing RNA-targeting drug development and synthetic biology design. The structural flexibility of RNA, which leads to the scarcity of experimentally determined data, complicates computational prediction efforts. Here we present RhoFold+, an RNA language model-based deep learning method that accurately predicts 3D structures of single-chain RNAs from sequences. By integrating an RNA language model pretrained on ~23.7 million RNA sequences and leveraging techniques to address data scarcity, RhoFold+ offers a fully automated end-to-end pipeline for RNA 3D structure prediction. Retrospective evaluations on RNA-Puzzles and CASP15 natural RNA targets demonstrate the superiority of RhoFold+ over existing methods, including human expert groups. Its efficacy and generalizability are further validated through cross-family and cross-type assessments, as well as time-censored benchmarks. Additionally, RhoFold+ predicts RNA secondary structures and interhelical angles, providing empirically verifiable features that broaden its applicability to RNA structure and function studies., Competing Interests: Competing interests: S.W. and L.Z. are the co-founders of Zelixir Biotech Co. Ltd. P.Y. is a co-founder, equity holder, board member and consultant of Ultivue, Inc., Spear Bio, Inc. and Digital Biology, Inc. J.J.C. is the founding scientific advisory board chair of Integrated Biosciences. F.W. is a co-founder of Integrated Biosciences. The other authors declare no competing interests., (© 2024. The Author(s).)

Acute myocardial infarction (AMI) is a leading cause of mortality among cardiovascular diseases, yet effective therapies for AMI are limited. Previous studies have suggested cardioprotective effects of columbianadin (CBN), but its specific role in AMI and the underlying mechanisms remain unclear. This study aims to investigate whether CBN influences AMI and to elucidate the underlying mechanisms. We conducted a network pharmacology analysis to investigate the relationship between CBN and AMI. The AMI model was established by ligating the left anterior descending (LAD) artery in C57BL/6J mice, which were subsequently administered CBN. Hypoxic H9c2 cells were utilized to evaluate the effects of CBN in vitro. Our study revealed that CBN treatment significantly reduced myocardial infarction in AMI mice. It enhanced mitochondrial function and suppressed autophagy flux in hypoxic H9c2 cells. Furthermore, CBN downregulated the expression of LC3, Beclin1, and Atg 5 genes and proteins. In response to CBN treatment, the phosphorylation levels of PI3K, Akt, and mTOR increased. Notably, RAPA attenuated the protective effect of CBN in enhancing the survival of hypoxic H9c2 cells and abolished its regulation of autophagy-related proteins via the PI3K/Akt/mTOR signaling pathway. In conclusion, CBN reduces myocardial damage by suppressing autophagy via the PI3K/Akt/mTOR signaling pathway in AMI mice and hypoxic H9c2 cells., (© 2024 John Wiley & Sons Ltd.)

The emergence and dissemination of mcr-1-positive Escherichia coli (MCRPEC) represent a critical public health threat. Here, we conducted a prospective analysis of MCRPEC isolates from wastewater treatment plants (WWTPs), local residents' fecal (LRF), and international airplane waste (IAW) to investigate their genetic characteristics and transmission patterns circulating in human-environment domains. The MCRPEC prevalence was 2.43 % in WWTPs, 1.37 % in IAW and 0.69 % in LRF. MCRPEC showed substantial genetic diversity, encompassing 61 sequence types (primarily ST1011, ST101, and ST2705), 7 plasmid types (primarily IncI2), 8 phylogroups (primarily A and B1), 9 mcr-1-flanked lineages (primarily L5), 6 clusters (primarily C2 and C4), diverse serotypes, and 61.95 % transposon-containing strains. The mcr-1 gene co-existed with 46 antibiotic resistance genes (ARGs) and 19 virulence factor genes (VFGs). Notably, 6 IncI2 plasmids carried the bla CTX-M , IS1380, and mcr-1 genes. MCRPEC from WWTPs harbored a greater number of ARGs (56.95 ± 5.99) but fewer VFGs (15.03 ± 6.40) compared to those from human-associated sources (LRF and IAW). ST1011, ST2705, IncHI2, and L7 were prevalent in WWTP-derived MCRPEC, whereas IncX4 and L3 were more common in human-derived MCRPEC. Genetic features such as ST101, ST48, IncI2, L4, L5, C2, and C4 were simultaneously present in strains from LRF, IAW, and WWTPs. Core genetic analyses also showed genetically similar MCRPEC strains across various geographic locations. The findings underscore the extensive dissemination, strong environmental adaptation, and clonal transmission of MCRPEC across diverse reservoirs, reinforcing the urgent need for coordinated multisectoral surveillance of human and environment interfaces to effectively mitigate further transmission., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Diabetic ulcers (DUs) present significant physical and psychological challenges to patients, while placing a significant economic burden on healthcare systems. Promoting the blood vessel regeneration is critical for ensuring the delivery of essential nutrients and oxygen to the injured area, thereby supporting the healing process. To gain insight into the complex molecular mechanisms that drive DUs healing, we performed a comprehensive analysis of single-cell transcriptomic data from healing and non-healing DU states. This analysis revealed a key role of Schlafen5 (SLFN5) signal in modulating key healing processes. SLFN5, a protein known to regulate cellular processes like migration, invasion, inflammation, and cell death, emerged as an important player. Yet, although it is prominent, the specific function of SLFN5 in diabetic skin wounds remained unclear. Our study discovered a marked elevation of SLFN5 levels in endothelial cells within DUs and its suppression notably mitigates the oxidative stress and endoplasmic reticulum stress (ERS)-mediated cell death pathways, including pyroptosis and apoptosis. This finding implies that excessive SLFN5 activity might obstruct wound closure by intensifying cellular stress reactions. Upon further investigation, we found that the antioxidant and cytoprotective effects were mediated through enhanced NRF2 activity, facilitated by the PI3K/Akt signaling pathway. Moreover, our investigation identified that c-Fos as a pivotal transcription factor governing SLFN5 transcription during the development of DUs, offering valuable insights into the regulation of SLFN5 expression. In diabetic mice model, SLFN5 knockdown accelerating wound healing, which was intervened by PI3K/Akt inhibitor. These results hold significant therapeutic potential, indicating that targeting SLFN5 may represent a novel and effective strategy for improving wound healing outcomes in patients with DUs., Competing Interests: Declaration of competing interest The authors have reported no potential conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Here we describe the data obtained by a successful proof-of-concept initiative to launch the first ocean color imager on board a CubeSat satellite and collect research-grade imagery at severalfold higher spatial resolution than any other ocean color satellite mission. The 3U CubeSat, named SeaHawk, flew at a nominal altitude of 585 km. Its ocean color sensor, HawkEye, collected 7,471 research-grade push-broom images of 230 × 780 km 2 at best-in-class 130 × 130 m 2 per pixel. The sensor is built with comparatively low-cost commercial off-the-shelf optoelectronics and was designed to match NASA SeaWiFS ocean color specifications, including wavelengths, bandwidths, and signal-to-noise ratios. HawkEye's design for ocean color remote sensing combined with its high spatial resolution make the imagery especially well-suited for coastal, estuarine, and limnological applications. Ultimately, the successful mission provided open access to a rich global dataset of calibrated and quality-controlled imagery for use in aquatic ecology and environmental change studies., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Myocardial ischemia-reperfusion injury (MIRI) is a significant risk factor for acute myocardial infarction and is closely associated with ferroptosis. This study aimed to identify key ferroptosis-related genes as potential diagnostic markers for MIRI and to explore their roles in immune infiltration and therapeutic targeting in myocardial tissue. We obtained single-cell RNA sequencing (scRNA-seq) and RNA-seq data on MIRI from the GEO database, applied Seurat and UMAP for data processing and clustering, and analyzed ligand-receptor interactions using CellPhoneDB. By scoring ferroptosis in cardiomyocytes, we identified differentially expressed genes and conducted GO and KEGG pathway analyses. A protein interaction network was then constructed using the STRING database, and seven key genes (Atp5h, Vdac2, Pkm, Cycs, Hspa8, Tpi1, Ldha) were identified through Lasso regression modeling, showing significant associations with immune responses. In vivo experiments in a mouse ischemia-reperfusion model confirmed the roles of these seven genes in MIRI via RT-qPCR. To further investigate the role of Hspa8 in ferroptosis and MIRI, siRNA knockdown experiments were performed in H9C2 rat cardiomyocytes, and its involvement in ferroptosis was validated by JC-1 staining and PCR analysis. This study reveals the importance of ferroptosis-related genes in MIRI through integrated bioinformatics and experimental approaches, offering new insights into diagnostic markers and immune-related therapeutic targets for MIRI., (© 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Controlling the redox states of single-walled carbon nanotubes (SWNTs) is important for the optimization of their real performances in various fields. By means of in situ photoluminescence (PL) spectroelectrochemical measurements, we report a successful modulation for the redox parameters (redox potentials and electrochemical band gap) of (6,5) and (7,5)SWNTs with a simple change in conjugated polymers (CPs) non-covalently wrapped on the nanotubes. The large shift in the band gap (187 meV for (6,5)SWNTs and 101 meV for (7,5)SWNTs) was connected to the prominent difference in the interactions between the CPs and SWNTs as suggested by molecular dynamics (MD) simulations, while a striking difference in the 𝜋-electrons states of CP/SWNTs enabled the tuning of SWNTs' electronic states. Asymmetrical modulation for the reduction potential (LUMO) and oxidation potential (HOMO) of the SWNTs was observed as well. Our results can be promising for a simple but precise control of the electric states of SWNTs., (© 2024 Wiley‐VCH GmbH.)

Proteolytic targeting chimera (PROTAC) represent an advanced strategy for targeting undruggable proteins, and the molecular warheads targeting E3 ligases play a crucial role. Recently, we explored an alkenyl oxindole warhead targeting the E3 ligase DCAF11 and sought to validate its potential. In this study, we synthesized a range of BRD4 PROTACs ( 8a - 8o , 14a-14f , 22a-22m ) with modified alkenyl oxindole warheads and developed a high-throughput screening system based on high-content imaging. We identified L134 ( 22a ) as a potent BRD4 degrader, achieving BRD4 degradation ( D max > 98%, DC 50 = 7.36 nM) and demonstrating antitumor activity. Mechanically, BRD4 degradation by L134 was mediated through the ubiquitin-proteasome system in a DCAF11-dependent manner. Therefore, this study provides a rapid screening method for effective PROTACs and highlights the PROTAC L134 based on alkenyl oxindole-DCAF11 pair as a promising candidate for treating BRD4-driven cancers.

Background and Aims: Tenecteplase (TNK) offers logistical advantages in stroke thrombolytic therapy with its single bolus administration compared with alteplase. We aim to investigate the real-world evidence regarding its safety and effectiveness in China., Methods: We conducted a retrospective study on patients receiving alteplase or TNK for acute ischaemic stroke (AIS) within 4.5 hours of onset between 1 March 2019 and 1 October 2023, from 18 stroke centres in China. Using propensity score matching (PSM), TNK-treated patients were matched 1:1 with alteplase-treated patients. The primary outcome was the rate of symptomatic intracranial haemorrhage (sICH) within 72 hours post-thrombolysis. Secondary outcomes comprised the rate of parenchymal haemorrhage type 2, any intracranial haemorrhage, any systematic bleeding and mortality at 90 days, as well as 24-hour National Institutes of Health Stroke Scale (NIHSS), early neurological improvement at 24 hours, modified Rankin Scale (mRS) shift, percentage of mRS 0-1 and mRS 0-2 at 90 days., Results: We identified 1113 patients with AIS who received TNK and 2360 patients who received alteplase. Following PSM, 1113 TNK-treated patients with AIS were matched to 1113 patients treated with alteplase. No significant differences were observed in rates of sICH (1.8% vs 1.98%, p=0.864) or other safety outcomes. Moreover, TNK-treated patients demonstrated a lower rate of any intracranial haemorrhage (OR: 0.51, 95% CI: 0.31 to 0.86, p=0.012). A higher proportion of patients achieving early neurological improvement at 24 hours (OR: 1.76, 95% CI: 1.48 to 2.09, p=0.000), better 90-day mRS (OR: 0.67, 95% CI: 0.57 to 0.79, p=0.000) as well as higher percentages of 90-day mRS 0-1 (OR: 1.27, 95% CI: 1.05 to 1.54, p=0.012) and mRS 0-2 (OR: 1.41, 95% CI: 1.14 to 1.75, p=0.001) compared with alteplase., Conclusions: Thrombolysis with TNK is not associated with an increased risk of sICH, and may result in better early neurological improvement and 90-day functional outcomes compared with alteplase in patients with AIS., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Norway spruce is an important coniferous species in boreal forests. Root and stem rot diseases caused by the necrotrophic pathogen Heterobasidion parviporum threaten the wood production of Norway spruce which necessitates the search for durable control and management strategies. Breeding for resistant traits is considered a viable long-term strategy. However, identification of potential resistant traits and markers remains a major challenge. In this study, short-term disease resistance screening was conducted using 218 Norway spruce clones from 17 families. Disease resistance was evaluated based on the size of necrosis lesion length following infection with the pathogen. A subset of needles/branches from clones with small (partial resistant) or large (susceptible) lesions were used for terpene analysis and transcriptomic profiling. The results revealed that the content of monoterpene linalool and 1,8-cineole and their respective encoded genes were significantly more abundant and highly expressed in the partial resistant group. Furthermore, linalool and 1,8-cineole were demonstrated to have inhibitory effect on the growth of the pathogen H. parviporum, with morphological distortion of the hyphae. RNAseq analysis revealed that transcript of pathogen genes involved in the regulation of carbohydrate metabolism and stress responses were significantly decreased in presence of the terpenes. The results suggest the relevance of monoterpenes together with jasmonic acid precursor and some genes involved in phenylpropanoid biosynthesis, as constitutive tolerance factors for Norway spruce tolerance against necrotrophic pathogen. The high level of necrosis related cell death gene expression might be factors critical for host susceptibility and disease development., (© 2024 The Author(s). Plant, Cell & Environment published by John Wiley & Sons Ltd.)

Previous reports showed that long non-coding RNA (lncRNA) participates in the development and progression of tumors. Nevertheless, the effect of LINC02139 and its mechanism on gastric cancer (GC) is still unknown. We revealed that LINC02139 is upregulated in GC cell lines and tissues and high LINC02139 expression was correlated with the advancement of GC in patients. Functionally, overexpression of LINC02139 promoted, while knockdown of LINC02139 impaired GC cell proliferation, migration, and invasion in vitro and impeded tumorigenesis in a tumor xenograft model in vivo. Mechanistically, LINC02139 directly bound to XIAP and increased the protein level by maintaining its protein stability through inhibition of the ubiquitination and proteasome-dependent degradation pathway. Importantly, the regulatory function of XIAP in LINC02139-mediated oncogenic effects was demonstrated. Both in vitro and in vivo experiments showed that LINC02139 and XIAP collaboratively modulate GC cell growth and apoptosis. Analysis of clinical GC tissues further confirmed the upregulation of XIAP and the positive association between LINC02139 and XIAP expression. These findings established LINC02139 as a driver of tumorigenesis and highlighted the crucial involvement of the LINC02139-XIAP axis in GC progression, suggesting its potential as a promising therapeutic target for combating GC advancement., Competing Interests: Competing interests The authors declare no competing interests. Ethical approval This study was approved by the Medical Ethics Committee of Nanfang Hospital, Southern Medical University, and Southern Medical University Experimental Animal Ethics Committee., (© 2024. The Author(s).)

Background: Currently available antiproprotein convertase subtilisin/kexin type 9 monoclonal antibodies can effectively decrease low-density lipoprotein cholesterol (LDL-C) levels, but require frequent dosing. Recaticimab is a novel humanized monoclonal antibody against proprotein convertase subtilisin/kexin type 9. In a phase 1b/2 trial, recaticimab as add-on to stable statins showed robust LDL-C reduction with a dosing interval up to every 12 weeks (Q12W) in patients with hypercholesterolemia., Objectives: REMAIN-2 (REcaticiMab Add-on therapy In patients with Nonfamilial hypercholesterolemia) aimed to assess the efficacy and safety of 48-week treatment with recaticimab as add-on therapy to statins in nonfamilial hypercholesterolemia., Methods: REMAIN-2 was a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial. During the run-in period, patients received stable moderate or high-intensity statin, with or without cholesterol absorption inhibitors (ezetimibe) or fenofibrate, for ≥4 weeks. Patients with an LDL-C of ≥1.8 mmol/L (if with atherosclerotic cardiovascular disease [ASCVD]) or ≥2.6 mmol/L (if without ASCVD) were then randomized (2:2:2:1:1:1) to receive recaticimab 150 mg every 4 weeks (Q4W), 300 mg every 8 weeks (Q8W), or 450 mg Q12W, or matching placebo injections (Q4W, Q8W, or Q12W) for 48 weeks. The primary efficacy endpoint was percentage change from baseline to week 24 in LDL-C level., Results: A total of 689 randomly assigned patients received treatment (mean age, 55.8 years; male, 64.4%; ASCVD history, 69.5%; concomitant ezetimibe, 11.2%; mean baseline LDL-C, 2.8 mmol/L). Percentage change in LDL-C from baseline to week 24 was significantly more pronounced with recaticimab vs placebo (P < 0.0001), with least-squares mean differences of -62.2% (95% CI: -67.0% to -57.4%), -59.7% (95% CI: -65.0% to -54.4%), and -53.4% (95% CI: -58.7% to -48.2%) for the 150 mg Q4W, 300 mg Q8W, and 450 mg Q12W regimens, respectively. The decreases in LDL-C with recaticimab were maintained through week 48. Secondary lipid variables, including non-high-density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a) also favored the recaticimab groups. During the treatment period, the incidence of treatment-related adverse events (28.5% vs 26.6%) and serious treatment-related adverse events (0.4% vs 0.4%) was similarly low in both the recaticimab and placebo groups., Conclusions: Recaticimab as add-on to stable statin therapy significantly decreased LDL-C levels at week 24 and sustained the decreases through week 48, providing a novel therapeutic alternative with a dosing interval of up to every 12 weeks in patients with nonfamilial hypercholesterolemia., Competing Interests: Funding Support and Author Disclosures This study was funded by Jiangsu Hengrui Pharmaceuticals. Dr Du has received research funding from Sanofi, AstraZeneca, and Bayer. Drs Zhong, Wang, and Guo were employees of Jiangsu Hengrui Pharmaceuticals at the time of the study. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

According to World Health Organization statistics, inappropriate medication has become an important factor affecting the safety of rational medication. In the gray area of medical insurance supervision, such as designated drugstores and medical institutions, there are lots of inappropriate medication phenomena regarding "big prescription for minor ailments." A traditional clinical decision support system is mostly based on established rules to regulate inappropriate prescriptions, which are not suitable for clinical environments and require intelligent review. In this study, we model the complex relationships between patients, diseases, and drugs based on medical big data to promote appropriate medication use. More specifically, we first construct the medication knowledge graph based on the historical prescription big data of tertiary hospitals and medical text data. Second, based on the medication knowledge graph, we employ a Gaussian mixture model to group patient population representation as physiological features. For diagnostic features, we employ pre-training word vector Bidirectional Encoder Representations from Transformers to enhance the semantic representation between diagnoses. In addition, to reduce adverse drug interactions caused by drug combinations, we employ a graph convolution network to transform drug interaction information into drug interaction features. Finally, we employ the sequence generation model to learn the complex relationships between patients, diseases, and drugs and provide an appropriate medication evaluation for doctor prescriptions in small hospitals from two aspects: drug list and medication course of treatment. In this study, we utilize the MIMIC III dataset alongside data from a tertiary hospital in Fujian Province to validate our model. The results show that our method is more effective than other baseline methods in the accuracy of the medication regimen prediction of rational medication. In addition, it achieved high accuracy in the appropriate medication detection of prescription in small hospitals., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Hong, Huang, Cai, Lin, Shao, Chen, Zhao and Yang.)

Metal alloys, pure titanium, metal-ceramics, and ceramic materials are used for fixed dental prostheses, which contained lead and potentially involved hepatotoxicity. To investigate the connection between fixed dental prostheses, blood lead levels, and liver function. A cross-sectional study enrolled 3624 American adults were conducted. Multivariate linear regression models and smooth curve fittings were used to describe correlations between the number of fixed dental prostheses, blood lead levels, and four liver function markers. Mediation analysis suggested an intermediary association of blood lead levels between prosthesis count and liver function. Here, number of fixed dental prostheses was significantly positive correlated with blood lead levels (p < 0.0001), but specifically negative correlated with alanine aminotransferase, lactate dehydrogenase, and gamma glutamyl transferase levels in males. Moreover, mediation analysis confirmed a mediating role for blood lead levels in the association between the number of prostheses and alanine aminotransferase levels in males only, with a mediation effect rate of 74.27% (p = 0.0020). An increased count of fixed prostheses is associated with changes in liver function markers in a gender-dependent manner, with blood lead levels serving as a potential mediator in males., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: The performance of intravenous tenecteplase in patients who had an acute ischaemic stroke with large/medium vessel occlusion or severe stenosis in an extended time window remains unknown. We investigated the promise of efficacy and safety of different doses of tenecteplase manufactured in China, in patients who had an acute ischaemic stroke with large/medium vessel occlusion beyond 4.5-hour time window., Methods: The CHinese Acute tissue-Based imaging selection for Lysis In Stroke-Tenecteplase was an investigator-initiated, umbrella phase IIa, open-label, blinded-endpoint, Simon's two-stage randomised clinical trial in 13 centres across mainland China. Participants who had salvageable brain tissue on automated perfusion imaging and presented within 4.5-24 hours from time of last seen well were randomised to receive 0.25 mg/kg tenecteplase or 0.32 mg/kg tenecteplase, both with a bolus infusion over 5-10 s. The primary outcome was proportion of patients with promise of efficacy and safety defined as reaching major reperfusion without symptomatic intracranial haemorrhage at 24-48 hours after thrombolysis. Assessors were blinded to treatment allocation. All participants who received tenecteplase were included in the analysis., Results: A total of 86 patients who had an acute ischaemic stroke identified with anterior large/medium vessel occlusion or severe stenosis were included in this study from November 2019 to December 2021. All of the 86 patients enrolled either received 0.25 mg/kg (n=43) or 0.32 mg/kg (n=43) tenecteplase, and were available for primary outcome analysis. Fourteen out of 43 patients in the 0.25 mg/kg tenecteplase group and 10 out of 43 patients in the 0.32 mg/kg tenecteplase group reached the primary outcome, providing promise of efficacy and safety for both doses based on Simon's two-stage design., Discussion: Among patients with anterior large/medium vessel occlusion and significant penumbral mismatch presented within 4.5-24 hours from time of last seen well, tenecteplase 0.25 mg/kg and 0.32 mg/kg both provided sufficient promise of efficacy and safety., Trial Registration Number: ClinicalTrials.gov Registry (NCT04086147, https://clinicaltrials.gov/ct2/show/NCT04086147)., Competing Interests: Competing interests: XC reported grant support from the National Natural Science Foundation of China and Science and Technology Commission of Shanghai Municipality. YS reported honoraria from Boehringer Ingelheim (China) Investment Co. The other authors report no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Drug-resistant bacteria infection and biofilm formation on the wound still pose a tremendous challenge in post-antibiotic era. It has been proposed that multimode synergetic antibacterial strategies may be employed to eradicate drug-resistant bacteria and biofilms effectively. In this study, we synthesized non-invasive antibacterial two-dimension (2D) composite nanosheet BPG using Ti 3 C 2 T x MXene and cationic borneol-guanidine based polymers (B-PGMA-Gu) via simple electrostatically co-assemble. BPG can target bacteria and efficiently eliminate Gram-positive bacteria Staphylococcus aureus ( S. aureus ), Gram-negative bacteria Escherichia coli ( E. coli ), and methicillin-resistant Staphylococcus aureus (MRSA) under 808 nm radiation. By combining the photothermal properties of Ti 3 C 2 T x MXene and the excellent membrane penetration ability of B-PGMA-Gu, MRSA biofilms can be effectively removed at 100 μg mL -1 under laser irradiation, resulting in a bactericidal efficiency of 99.1%. This method offers a more effective and rapid non-antibiotic method for removing biofilms.

Individuals with a family history of alcohol or other substance use disorders (FH+) are at increased risk for developing alcohol and other substance use disorders (AUD/SUD) compared to individuals with no such family histories (FH-). FH+ young adults have blunted stress reactivity, lower cognitive performance and altered frontal white matter microstructure compared to FH- controls. We hypothesized that family history of AUD/SUD disrupts neuroendocrine regulation of the immune system in FH+ individuals, resulting in altered blood immune cell composition, inflammation and neurocognitive alterations that, ultimately, increases risk for AUD/SUD and associated psychopathology. We examined white blood cell (WBC) parameters derived from complete blood counts in FH+ (n = 37) and FH- (n = 77) young adults without AUD/SUD to test if immune system dysregulation is present in FH+ individuals. The total WBC count, number of neutrophils and number of monocytes and associated systemic inflammatory response index (SIRI) were significantly increased in the FH+ group. Further, WBC, neutrophil, monocyte counts and SIRI values were all positively correlated with FH density (number of biological parents and grandparents with AUD/SUD). These novel data are the first to identify an association between family history of AUD/SUD and increased circulating leukocytes, which is likely indicative of immune dysregulation in FH+ young adults prior to onset of AUD/SUD. Additional studies are warranted to characterize the functional relevance of the observed immune cell composition in FH+ individuals, but the notion that inexpensive and widely available blood tests may help identify addiction risk could be transformative., (© 2024 The Author(s). Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

The Adolescent Brain and Cognitive Development (ABCD) project is the largest study of adolescent brain development. ABCD longitudinally tracks 11,868 participants aged 9-10 years from 21 sites using standardized protocols for multi-site MRI data collection and analysis. While the multi-site and multi-scanner study design enhances the robustness and generalizability of analysis results, it may also introduce nonbiological variances including scanner-related variations, subject motion, and deviations from protocols. ABCD imaging data were collected biennially within a period of ongoing maturation in cortical thickness and integrity of cerebral white matter. These changes can bias the classical test-retest methodologies, such as intraclass correlation coefficients (ICC). We developed a site-wise adaptive ICC (AICC) to evaluate the reliability of imaging-derived phenotypes while accounting for ongoing brain development. AICC iteratively estimates the population-level age-related brain development trajectory using a weighted mixed model and updates age-corrected site-wise reliability until convergence. We evaluated the test-retest reliability of regional fractional anisotropy (FA) measures from diffusion tensor imaging and cortical thickness (CT) from structural MRI data for each site. The mean AICC for 20 FA tracts across sites was 0.61 ± 0.19, lower than the mean AICC for CT in 34 regions across sites, 0.76 ± 0.12. Remarkably, sites using Siemens scanners consistently showed significantly higher AICC values compared with those using GE/Philips scanners for both FA (AICC = 0.71 ± 0.12 vs. 0.46 ± 0.17, p < 0.001) and CT (AICC = 0.80 ± 0.10 vs. 0.69 ± 0.11, p < 0.001). These findings demonstrate site-and-scanner related variations in data quality and underscore the necessity for meticulous data curation in subsequent association analyses., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

RNAs represent a class of programmable biomolecules capable of performing diverse biological functions. Recent studies have developed accurate RNA three-dimensional structure prediction methods, which may enable new RNAs to be designed in a structure-guided manner. Here, we develop a structure-to-sequence deep learning platform for the de novo generative design of RNA aptamers. We show that our approach can design RNA aptamers that are predicted to be structurally similar, yet sequence dissimilar, to known light-up aptamers that fluoresce in the presence of small molecules. We experimentally validate several generated RNA aptamers to have fluorescent activity, show that these aptamers can be optimized for activity in silico, and find that they exhibit a mechanism of fluorescence similar to that of known light-up aptamers. Our results demonstrate how structural predictions can guide the targeted and resource-efficient design of new RNA sequences., Competing Interests: Competing interests: J.J.C. is the founding scientific advisory board chair of Integrated Biosciences. F.W. is a co-founder of Integrated Biosciences. S.O. has an equity interest in Integrated Biosciences. The other authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

The synthesis of multiple narrow optical spectral lines, precisely and independently tuned across the near- to mid-infrared region, is a pivotal research area that enables selective and real-time detection of trace gas species within complex gas mixtures. However, existing methods for developing such light sources suffer from limited flexibility and very low pulse energy, particularly in the mid-infrared domain. Here, we introduce a concept that is based on the combination of an appropriate design of near-infrared fiber laser pump and cascaded configuration of gas-filled anti-resonant hollow-core fiber technology. This concept enables the synthesis of multiple independently tunable spectral lines, with >1 μJ high pulse energies and a few nanoseconds pulse width in the near- and mid-infrared regions. The number and wavelengths of the generated spectral lines can be dynamically reconfigured. A proof-of-concept laser beam synthesized of two narrow spectral lines at 3.99 µm and 4.25 µm wavelengths is demonstrated and combined with photoacoustic modality for real-time SO 2 and CO 2 detection. The proposed concept also constitutes a promising way for infrared multispectral microscopic imaging., (© 2024. The Author(s).)

Proper development of the placenta, the transient support organ forms after embryo implantation, is essential for a successful pregnancy. However, the regulation of trophoblast invasion, which is most important during placentation, remains largely unknown. Here, rats, mice, and pigs are used as biomedical models, used scRNA-seq to comparatively elucidate the regulatory mechanism of placental trophoblast invasion, and verified it using a human preeclampsia disease model combined with scStereo-seq. A dual-featured type of immune-featured trophoblast (iTrophoblast) is unexpectedly discovered. Interestingly, iTrophoblast only exists in invasive placentas and regulates trophoblast invasion during placentation. In a normally developing placenta, iTrophoblast gradually transforms from an immature state into a functional mature state as it develops. Whereas in the developmentally abnormal preeclamptic placenta, disordered iTrophoblast transformation leads to the accumulation of immature iTrophoblasts, thereby disrupting trophoblast invasion and ultimately leading to the progression of preeclampsia., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Owing to a lack of specific biological functions, bacterial cellulose (BC) has been restricted in its application to the field of active packaging. In this study, we developed antimicrobial packaging materials using foaming BC (FBC) with chitosan (CS) and applied it to the preservation of chilled sea bass. The material property analysis demonstrated that 1.5 % CS/FBC maintained a high water content of 91 %, a swelling ratio of 75.6 %, great stress of 1.61 MPa, and great strain of 1.87 %. CS incorporation into FBC also decreased its crystallinity from 73.39 % to 69.3 %. Meanwhile, 1.5 % CS/FBC also provided great antimicrobial ability against Escherichia coli and Staphylococcus aureus by approximately 2 log colony-forming units/mL inhibition utilizing contact-killing. Results of the preservation assessment indicated that 1.5 % CS/FBC efficiently inhibited Shewanella putrefaciens growth, reduced total volatile basic nitrogen release, and slightly inhibited lipid oxidation. Based on the above results, CS/FBC is an ecofriendly biomaterial produced from a microorganism that possesses high absorbency and strong antibacterial properties, making it suitable for development as antibacterial active packaging., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Apolipoprotein E ε4 (APOE4) is a strong genetic risk factor of Alzheimer's disease and metabolic dysfunction. However, whether APOE4 and markers of metabolic dysfunction synergistically impact the deterioration of white matter (WM) integrity in older adults remains unknown. In the UK Biobank data, we conducted a multivariate analysis to investigate the interactions between APOE4 and 249 plasma metabolites (measured using nuclear magnetic resonance spectroscopy) with whole-brain WM integrity (measured by diffusion-weighted magnetic resonance imaging) in a cohort of 1917 older adults (aged 65.0-81.0 years; 52.4 % female). Although no main association was observed between either APOE4 or metabolites with WM integrity (adjusted P > 0.05), significant interactions between APOE4 and metabolites with WM integrity were identified. Among the examined metabolites, higher concentrations of low-density lipoprotein and very low-density lipoprotein were associated with a lower level of WM integrity (b=-0.12, CI=-0.14,-0.10) among APOE4 carriers. Conversely, among non-carriers, they were associated with a higher level of WM integrity (b=0.05, CI=0.04,0.07), demonstrating a significant moderation role of APOE4 (b =-0.18, CI=-0.20,-0.15, P<0.00001)., Competing Interests: Declaration of Competing Interest The authors declare that this manuscript, in its entirety or in part, has not been previously published or is under consideration for publication elsewhere, in any language. Each author acknowledges their responsibility for the content presented. Furthermore, the authors affirm that, if accepted, the manuscript will not be reproduced or published in the same form, whether in English or any other language, including electronic formats, without obtaining written consent from the copyright-holder. This submission adheres to ethical standards, and the authors stand committed to exclusive publication rights for the work., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Phenanthrene (Phe) is a commonly occurring polycyclic aromatic hydrocarbon (PAH) found in various food sources and drinking water. Previous studies have shown that long-term exposure to Phe in male mice leads to insulin resistance in a dose-dependent manner. However, the effect of Phe on glucose homeostasis in female mice remains unknown. To address this knowledge gap, female Kunming mice were exposed to Phe through their drinking water at concentrations of 0.05, 0.5, and 5 ng/mL. After 270 d of exposure, we surprisingly discovered a low-dose effect of Phe on insulin resistance in female mice, which differed from the effect observed in male mice and showed sexual dimorphism. Specifically, insulin resistance was only observed in the 0.05 ng/mL treatment, and this low-dose effect was also reflected in the concentration of Phe in white adipose tissue (WAT). Differences in metabolic enzyme activities in the liver may potentially explain this effect. The observed sexual dimorphism in Phe exposure could be attributed to variations in estrogen (E2) level and estrogen receptor beta (ERβ) expression in WAT. These findings highlight the association between environmental factors and the development of insulin resistance, emphasizing the pathogenic effect of even low doses of Phe. Moreover, sex dependent-effect should be given more attention when studying the toxic effects of environmental pollutants., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Continuous myelination of cerebral white matter (WM) during adolescence overlaps with the formation of higher cognitive skills and the onset of many neuropsychiatric disorders. We developed a miniature-pig model of adolescent brain development for neuroimaging and neurophysiological assessment during this critical period. Minipigs have gyroencephalic brains with a large cerebral WM compartment and a well-defined adolescence period., Methods: Eight Sinclair™ minipigs (Sus scrofa domestica) were evaluated four times during weeks 14-28 (40, 28 and 28 days apart) of adolescence using monocular visual stimulation (1 Hz)-evoked potentials and diffusion MRI (dMRI) of WM. The latency for the pre-positive 30 ms (PP30), positive 30 ms (P30) and negative 50 ms (N50) components of the flash visual evoked potentials (fVEPs) and their interhemispheric latency (IL) were recorded in the frontal, central and occipital areas during ten 60-second stimulations for each eye. The dMRI imaging protocol consisted of fifteen b-shells (b = 0-3500 s/mm 2 ) with 32 directions/shell, providing measurements that included fractional anisotropy (FA), radial kurtosis, kurtosis anisotropy (KA), axonal water fraction (AWF), and the permeability-diffusivity index (PDI)., Results: Significant reductions (p < 0.05) in the latency and IL of fVEP measurements paralleled significant rises in FA, KA, AWF and PDI over the same period. The longitudinal latency changes in fVEPs were primarily associated with whole-brain changes in diffusion parameters, while fVEP IL changes were related to maturation of the corpus callosum., Conclusions: Good agreement between reduction in the latency of fVEPs and maturation of cerebral WM was interpreted as evidence for ongoing myelination and confirmation of the minipig as a viable research platform. Adolescent development in minipigs can be studied using human neuroimaging and neurophysiological protocols and followed up with more invasive assays to investigate key neurodevelopmental hypotheses in psychiatry., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare. All co-authors have seen and agree with the contents of the manuscript and there is no financial interest to report., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Pulmonary fibrosis (PF) is a persistent interstitial lung condition for which effective treatment options are currently lacking. Zerumbone (zerum), a humulane sesquiterpenoid extracted from Zingiber zerumbet Smith, has been documented in previous studies to possess various pharmacological benefits. The aim of this study was to observe and investigate the therapeutic effects and mechanisms of zerum on pulmonary fibrosis. We utilized a transforming growth factor (TGF)-β1-induced human lung fibroblast (MRC-5) activation model and a bleomycin-induced pulmonary fibrosis mouse model. Cell counting kit 8 (CCK8) and cell migration assays were performed to assess the effects of zerum on MRC-5 cells. Masson's trichrome, Hematoxylin and Eosin (HE), and Sirius Red staining were conducted for pathological evaluation of lung tissue. Western blot experiments were conducted to measure the protein expression levels of Collagen I, α-SMA, Nrf2, and SIRT1. Immunofluorescence and immunohistochemistry assays were used to detect the expression of reactive oxygen species (ROS), Nrf2, and α-SMA. ELISA was employed to measure the levels of MDA, SOD, and GSH-Px. Our findings from in vitro and in vivo studies demonstrated that zerum significantly inhibited the migration ability of TGF-β1-induced MRC-5 cells, reduced ROS production in TGF-β1-induced MRC-5 cells and pulmonary fibrosis mice, and decreased the expression of Collagen I and α-SMA proteins. Additionally, zerum activated the SIRT1/Nrf2 signaling pathway in TGF-β1-induced MRC-5 cells and pulmonary fibrosis mice. Knockdown of SIRT1 abolished the anti-fibrotic effects of zerum. These results suggest that zerum inhibits TGF-β1 and BLM-induced cell and mouse pulmonary fibrosis by activating the SIRT1/Nrf2 pathway., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Immune thrombocytopenia (ITP) is a prevalent autoimmune bleeding disorder, with the primary objective of treatment being the prevention of bleeding. Clinical investigations have indicated that individuals with ITP face an elevated risk of thrombosis, and the occurrence of thromboembolic events in ITP patients can be attributed to a multitude of factors. However, establishing a definitive causal relationship between ITP and thrombosis remains challenging., Methods: A two-sample Mendelian randomization (MR) study utilizing summary data from FinnGen consortium and UK Biobank was undertaken to investigate the causal association between ITP and thrombosis. The primary analysis employed the inverse-variance weighted (IVW) method, while supplementary analyses were conducted using the MR-Egger, weighted median, and MR-PRESSO approaches., Results: Based on IVW method, there was a statistically significant but small positive correlation between ITP and thrombosis. Specifically, ITP patients exhibited a suggestive positive correlation with myocardial infarction and deep-vein thrombosis. However, our investigation did not identify any causal relationship between ITP and cerebral infarction, arterial embolism, other arterial embolisms, pulmonary embolism, thrombophlebitis, or portal vein thrombosis. Sensitivity analyses further confirmed the accuracy and robustness of these findings., Conclusions: This study presents empirical support for the causal relationship between ITP and thrombosis. It is important to note that a diminished platelet count does not serve as a preventive measure against thrombus formation. Consequently, when managing a newly diagnosed ITP patient, clinicians need to be aware that there is a slight elevation in the risk of thrombosis during treatment., Competing Interests: Declaration of competing interest The authors report no relationships that could be construed as a conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Background: Vascular degeneration is an important cause of brain damage in aging. Assessing the functional properties of the cerebral vascular system may aid early diagnosis and prevention., Purpose: To investigate the relationships between potential vascular functional markers and vascular risks, brain parenchymal damage, and cognition., Study Type: Retrospective., Subjects: Two hundred two general community subjects (42-80 years, males/females: 127/75)., Field Strength/sequence: 3 T, spin echo T1W/T2W/FLAIR, resting-state functional MRI with an echo-planar sequence (rsfMRI), pseudo-continuous arterial spin labeling (pCASL) with a three-dimensional gradient-spin echo sequence., Assessment: Cerebral blood flow (CBF) in gray matter calculated using pCASL, blood transit times calculated using rsfMRI, and the SD of internal carotid arteries signal (ICA std ) calculated using rsfMRI; visual assessment for lacunes; quantification of white matter hyperintensity volume; permutation test for quality control; collection of demographic and clinical data, Montreal Cognitive Assessment, Mini-Mental State Examination., Statistical Tests: Kolmogorov-Smirnov test; Spearman rank correlation analysis; Multivariable linear regression analysis controlling for covariates; The level of statistical significance was set at P < 0.05., Results: Age was negatively associated with ICA std (β = -0.180). Diabetes was associated with longer blood transit time from large arteries to capillary bed (β = 0.185, adjusted for age, sex, and intracranial volume). Larger ICA std was associated with less presence of lacunes (odds ratio: 0.418, adjusted for age and sex). Higher gray matter CBF (β = 0.154) and larger ICA std (β = 0.136) were associated with better MoCA scores (adjusted for age, sex, and education)., Data Conclusion: Prolonged blood transit time, decreased ICA std , and diminished CBF were associated with vascular dysfunction and cognitive impairment. They may serve as vascular functional markers in future studies., Evidence Level: 3 TECHNICAL EFFICACY: Stage 3., (© 2024 International Society for Magnetic Resonance in Medicine.)

Crocus sativus L. is a perennial crop for its valuable active compounds. Plant-associated microbes impact on the quality and efficacy of medicinal herbs by promoting bioactive components accumulation. However, how microbes influence the accumulation of bioactive components in saffron have not been well studied. Here, the microbiome in C. sativus derived from 3 core production areas were deciphered by 16S rDNA sequencing and the relationship between endophytes and bioactive ingredients were further investigated. The main results are as follows: (1) Both Comamonadaceae and Burkholderiaceae were positively correlated with the content of bioactive components in the stigmas. (2) The synthesis of crocin was positively correlated with Xanthomonadaceae, negatively correlated with Lachnospiraceae and Prevotellaceae. Therefore, further investigation is required to determine whether Xanthomonadaceae plays an unknown function in the synthesis of crocin. These findings provide guidelines for disentangling the function of endophytes in the production of bioactive ingredients and thus for microbe-mediated breeding., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Nicotine addiction, a multifaceted neuropsychiatric disorder, profoundly impacts brain functions through interactions with neural pathways. Despite its significance, the impact of tobacco smoking on the whole-brain functional connectome remains largely unexplored., Methods: We conducted a whole-brain analysis on 24,539 adults aged 40 and above from the UK Biobank cohort. Subjects were categorized into individuals who use nicotine and who do not use nicotine based on current and chronic tobacco smoking information. Functional connectivity was assessed using resting-state functional magnetic resonance imaging (rfMRI). We employed a network analysis method to assess the systematic effects of tobacco smoking on brain connectome by identifying subnetworks that show nicotine-use-related differences., Results: Our analyses revealed two nicotine-use-related subnetworks with distinct network structure (permutation p-value < 0.001). In the first network, there is a significant decrease in resting-state functional connectivity (rsFC) between the basal ganglia regions (e.g., nucleus accumbens) and 73% of the remaining brain regions, emphasizing the central hub role of basal ganglia in addictive smoking behaviors. Additionally, a data-driven subnetwork mainly involving regions from frontal and occipital lobes, showed reduced rsFC among individuals who use nicotine., Conclusion: The results suggest significant alterations in the communication and coordination among the basal ganglia and the broader network of brain regions. The observed changes in rsFC indicate a widespread disruption in the connectivity patterns associated with nicotine use., Implications: This study identifies rsFC subnetworks related to chronic nicotine use through whole-brain connectome analysis. The findings confirm that widespread alterations in rsFC are centered around hub nodes within the basal ganglia, including bilateral nucleus accumbens, putamen, caudate, and globus pallidus. In addition, our analysis found a clique-forming subnetwork vulnerable to tobacco smoking consisting of regions from the visual, dorsal/ventral attention, and frontoparietal networks., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

To manipulate the protein concentration at a certain functional state through chemical stabilizers is crucial for protein-related studies. It not only plays a key role in protein structure analysis and protein folding kinetics, but also affects protein functionality to a large extent and thus has wide applications in medicine, food industry, etc. However, due to concerns about side effects or financial costs of stabilizers, identifying optimal strategies for enhancing protein stability with a minimal amount of stabilizers is of great importance. Here, we prove that either for the fixed terminal time (including both finite and infinite cases) or for the free one, the optimal control strategy for stabilizing the folding intermediates with a linear strategy for stabilizer addition belongs to the class of bang-bang controls. The corresponding optimal switching time is derived analytically, whose phase diagram with respect to several key parameters is explored in detail. The bang-bang control will be broken when nonlinear strategies for stabilizer addition are adopted. Moreover, the above theory is applied to the stabilization of erythropoietin by ten different kinds of chemicals, providing theoretical guidance for the selection and rational usage of stabilizers. Our current study on optimal strategies for protein stabilizers not only offers deep insights into the general picture of protein folding kinetics but also provides valuable theoretical guidance on treatments for protein-related diseases in medicine., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

Chlorophyll degradation is a characteristic process of leaf senescence. Two mutant lines, which showed green leaves and seeds during senescence, were identified by screening a Tnt-1 retrotransposon-tagged population of Medicago truncatula. Genetic and molecular analyses indicated that the mutated gene is NON-YELLOW COLORING 1 (MtNYC1) in M. truncatula. MtNYC1 encoded a chlorophyll b reductase, characterized by three transmembrane domains and a catalytic site (Y***K). Our investigation further identified three splicing variants of MtNYC1, encoding a full-length protein (MtNYC1A) and two truncated proteins (MtNYC1B, MtNYC1C). Genetic evidence indicated that the catalytic site and the third transmembrane domain were critical domains for chlorophyll b reductase. The coordinated action of three splicing variants plays a pivotal role in the degradation of chlorophyll during the senescence of leaves. This discovery provides precise target sites for the development of stay-green legume cultivars., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aims: To evaluate the global cardiovascular disease (CVD) burden attributable to metabolic risks in 204 countries and territories from 1990 to 2021., Methods and Results: Following the methodologies used in the Global Burden of Disease Study 2021, this study analyzed CVD deaths and disability-adjusted life-years (DALYs) attributable to metabolic risks by location, age, sex, and socio-demographic index (SDI). In 2021, metabolic risks accounted for 13.59 million CVD deaths (95% UI 12.01 to 15.13) and 287.17 million CVD DALYs (95% UI 254.92 to 316.32) globally, marking increases of 63.3% and 55.5% since 1990, respectively. Despite these increases, age-standardised mortality and DALY rates have significantly declined. The highest age-standardised rates of metabolic risks-attributable CVD mortality and DALYs were observed in Central Asia and Eastern Europe, while the lowest rates were found in High-income Asia Pacific, Australasia, and Western Europe, all of which are high SDI regions. Among the metabolic risks, high systolic blood pressure emerged as the predominant factor, contributing to the highest numbers of CVD deaths [10.38 million (95% UI 8.78 to 12.03)] and DALYs [14.52 million (95% UI 180.42 to 247.57)] in 2021, followed by high LDL cholesterol., Conclusion: Our study highlights the persistent and significant impact of metabolic risks on the global CVD burden from 1990 to 2021, emphasizing the need of designing public health strategies that align with regional healthcare capacities and demographic differences to effectively reduce these effects through enhanced international collaboration and specific policies., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Constructing a uniform coating of alkali metal-containing fast ionic conductors is crucial for realizing multifunctional responses and functionalities. However, the uncontrolled coprecipitation of alkali and transition metal ions, stemming from their significant difference in reactivity, poses a significant challenge in pursuing homogeneous and continuous nanoshells for fast ionic conductors. Here, we report a versatile peroxide-based kinetics-controlled coating approach for constructing alkali metal-containing fast ionic conductors using LiNbO 3 as a proof-of-concept. Hydrogen peroxide (H 2 O 2 ) was employed as an innovative precipitant, and the deposition kinetics could be precisely tuned by adjusting the pH value of the solution to facilitate the coprecipitation of the transition metal and ammonium/hydrogen ions. The latter could subsequently be exchanged with lithium ions and transformed into uniform LiNbO 3 nanoshells after low-temperature annealing (280 °C). The obtained LiNbO 3 coating layers are continuous, thickness-tunable, and exhibit significantly higher ionic conductivity, 2 orders of magnitude greater than conventional counterparts. This enhancement enables solid-state batteries with excellent cycling and rate performance. Furthermore, this method is extendable to various alkali metal-based (Li, Na, and K) fast ionic conductor nanoshells, injecting new vitality into the advanced applications of fast ionic conductors in various battery systems.

Acute ischemic stroke (AIS) is one of the most predominant causes of mortality and disability in China. Significant uncertainties in stroke diagnosis and time of onset have resulted in inconsistent evidence on the association between ambient air pollution and the risk of AIS. The present study aimed to evaluate the impact of air pollution on AIS onset based on high time-resolution air pollution data and a stroke-specific registry across the past five years. Hourly concentrations of PM 2.5 , PM 10 , O 3 , SO 2 , CO, NO 2 and nitrous acid (HONO) were monitored from 2017 to 2021, with which a distributed lag non-linear model and conditional logistic regression models coupled with a time-stratified case-crossover design were applied to 106,623 AIS cases recorded in the Shanghai Stroke Service (4S) database during the study period. Results from the conditional logistic regression models indicate that acute exposure to PM 2.5 , PM 10 , SO 2 , NO 2 and HONO was found to be associated with AIS onset, respectively. The corresponding cumulative excessive risks of AIS onset were 0.8 %, 1 %, 2.4 %, 2.1 % and 1.8 % for each interquartile range increase in the respective concentration. The longest lag-effect (up to 13 h) was observed for reactive nitrogen species (RNS), such as NO 2 and HONO, which remained robust in two-pollutant models. Similar important role of RNS in AIS onset were confirmed by the distributed lag non-linear model. By demonstrating the transient effect of ambient air pollution on AIS, especially the relationships between RNS and AIS for the first time, our study provides stringent evidence for future mitigation strategies for pollution emission and public health., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

The present study investigated the effects of water extracts of Artemisia annua L. (WEAA) on rumen immune and antioxidative indexes, fermentation parameters and microbial diversity in lambs. A total of 32 3-month-old Dorper × Han female lambs having comparable body weights (24±0.09 kg) were selected and were randomly assigned to four treatments, with eight repetitions for each treatment. The basal diet, consisting of 45% concentrate and 55% forage, was solely provided to the control group. For the other treatment groups, the basal diet was supplemented with WEAA at dosages of 500, 1000, and 1500 mg/kg diet, respectively. Rumen tissue samples were collected for the analysis of immune and antioxidative parameters, as well as related gene expression. Rumen fluid samples were collected to assess rumen fermentation parameters on days 30 and 60 and to evaluate the microbiota on day 60. Results showed that WEAA supplementation linearly or quadratically increased the content of sIgA, IL-4, IL-2 and the gene expression level of MyD88, IκB-α, IL-4, COX-2, iNOS in rumen tissue ( p < 0.05), as well as the bacteria negatively associated with IL-6 ( g&#95; [Eubacterium] &#95;cellulosolvens&#95;group ). Furthermore, the addition of WEAA linearly or quadratically increased rumen T-SOD, GSH-Px ( p < 0.05) and the gene expression level of Nrf2, SOD2, GSH-Px, HO-1 ( p < 0.05), and decreased the rumen concentration of malondialdehyde (MDA) and gene expression level of Keap1 ( p < 0.05), as well as the bacteria positively associated with T-AOC, T-SOD and GSH-Px ( g&#95;Lachnospiraceae&#95;NK3A20&#95;group , g&#95;Saccharofermentans , g&#95;&#95;Marvinbryantia , g&#95;unclassified&#95;f&#95;Eggerthellaceae ). The supplementation of WEAA caused the concentration of microprotein (MCP), total volatile fatty acids (TVFA), propionate to increase either linearly or quadratically, while reducing the concentration of NH3-N and the acetate/propionate ratio (A:P) in rumen fluid ( p < 0.05). The addition of WEAA linearly or quadratically increased the abundance of Actinobacteriota, Cyanobacteria and Lachnospiraceae&#95;NK3A20&#95;group ( p < 0.10), and g&#95;&#95;Lachnospiraceae&#95;NK3A20&#95;group , g&#95;Saccharofermentans , g&#95;Marvinbryantia , g&#95;Bifidobacterium were significantly abundant as specific microflora in the 1000 mg/kg WEAA supplementation group. In conclusion, dietary inclusion of 1000 mg/kg WEAA improved the rumen immune function, antioxidant status, rumen fermentation, and composition of rumen microbes in lambs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Gang, Gao, Zhao, Xu, Xing, Jin, Hong, Yan and Shi.)

Delayed graft function (DGF) is a type of acute renal failure that is closely linked to the immune system. The objective of this study is to investigate immune trends during the perioperative period of renal transplantation and compare the variations between patients with DGF and immediate graft function (IGF). A total of 48 kidney transplant patients were enrolled. Parameters including stimulated adenosine triphosphatase concentrations (sATP), nonstimulated ATP concentrations, white blood cells, and lymphocyte count were assessed. Patients were categorized into the DGF or IGF group. Clinical information and changes in immune markers were compared. Receiver operating characteristic analysis was performed to determine the sensitivity and specificity in predicting DGF. Additionally, separate immune function analyses were conducted for the 3 infection cases. Following induction immunosuppressive therapy, white blood cells, and neutrophil count showed a significant initial increase followed by a gradual decline. Lymphocyte count, nonstimulated ATP concentrations, and sATP exhibited an initial significant decrease followed by a slow recovery. Immune markers between the DGF and IGF groups were significantly different at day 4 after renal transplantation. Only sATP levels at day 4 after renal transplantation (area under the curve = 0.731, sensitivity = 0.864, specificity = 0.684) demonstrated predictive value for DGF occurrence. Among the 3 infection cases, 2 cases exhibited persistently decreased sATP levels and died within the first month and 6 months, while the remaining case showed a recovery of sATP levels at D9 and survived. These findings indicate that sATP level can potentially serve as a biomarker reflecting the impact of immunosuppressants. Poor recovery of sATP may be associated with DGF, infection, or even mortality., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Dysregulation of macrophage polarization can prevent the invasion of trophoblast cells and further limit spiral artery remodeling in preeclampsia (PE). However, its mechanism is obscure. HTR8-/Svneo cells were cultured under normoxic or hypoxic conditions and extracellular vesicles (EVs) in the culture supernatants were extracted. Next, the cells were incubated with those EVs to investigate their effects on trophoblasts. A co-culture system consisting of HTR8-/Svneo cells and macrophages was used to reveal how the trophoblast-derived EVs affected the macrophage subtype. Finally, a PE mouse model and miR-141-3p knockout mice were used to verify the function of miR-141-3p in PE. Hypoxia induced abnormal increases in the levels of miR-141-3p in HTR8-/Svneo cells and EVs. EVs from hypoxia-treated HTR8-/Svneo cells could downregulate PTEN, a potential target of miR-141-3p, and inhibit trophoblast mitophagy and invasion. However, HTR8-/Svneo cells transfected with an miR-141-3p inhibitor could attenuate the influence of EVs. In an HTR8-/Svneo cell plus macrophage co-culture system, hypoxia-pretreated cells promoted the transformation of macrophages into the M1-phenotye, and HTR8-/Svneo invasion was inhibited by the macrophages. MiR-141 from EVs could target and downregulate dual specificity phosphatase 1 (DUSP1) expression in macrophages, induce formation of the M1 macrophage phenotype in THP-1 cells, downregulate DUSP1 expression, and upregulate TAB2/TAK1 signaling. These results were also demonstrated in normal pregnant mice and PE pregnant mice. A hypoxic environment could upregulate miR-141 expression in the EVs of HTR8-/Svneo cells, and THP-1-derived macrophages could uptake EVs releasing miR-141 to downregulate DUSP1 expression and induce the formation of M1 macrophages, which can lead to the development of PE., (© 2024. The Author(s).)

None declared.Conflict of interestPlantation of Chinese fir, a popular woody tree species, faces sustainable issues such as nutrient deficiency and increasing disease threat. Rhizosphere and endophytic bacteria play important roles in plant' nutrient absorption and stress alleviation. Our understanding on the microbiome structure and functions are proceeding rapidly in model plants and some crop species. Yet, the spatial distribution and functional patterns of the bacteriome for the woody trees remain largely unexplored. In this study, we collected rhizosphere soil, non-rhizosphere soil, fine root, thick root and primary root samples of Chinese fir, and investigated the structure and distribution of bacteriome, as well as the beneficial effects of endophytic bacterial isolates. We discovered that Burkholderia and Paraburkholderia genera were overwhelmingly enriched in rhizosphere soil and the abundance of Pseudomonas genus was significantly enhanced in fine root. By isolating and testing the nutrient absorption and pathogen antagonism functions of representative endophytic bacteria species in Pseudomonas and Burkholderia, we noticed that P-solubilising functional isolates was enriched in fine root, while pathogen antagonism isolates was enriched in thick root. As a conclusion, our study revealed that the endophytic and rhizosphere environments of Chinese fir hold distinct structure and abundance of bacteriome, with potential specific functional enrichment of some bacterial clades. These findings assist us to further study the potential regulation mechanism of endophytic functional bacteria by the host tree, which will contribute to beneficial microbe application in forestry plantation and sustainable development., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Background: The purpose of this study was to investigate the effectiveness of allergen-specific immunotherapy (AIT) on small airway dysfunction (SAD) and the underlying mechanism with a special focus on basophils., Methods: Sixty-five children with mild to moderate asthma who were under regular inhaled corticosteroid (ICS) treatment for more than 1 year but whose FEF 75 remained below 65% of the predicted value and had positive results for serum Der p or Der f were enrolled. Children with asthma underwent house dust mite (HDM) subcutaneous immunotherapy (SCIT) treatment for 1 year. Clinical symptoms and lung function were evaluated every 3 months during HDM SCIT treatment. Basophil activation test (BAT) was carried out before and after HDM SCIT treatment. RNA sequencing was performed in isolated basophils from peripheral blood after 6 months of HDM SCIT treatment, followed by GO term and KEGG pathway enrichment analysis between patients with and without HDM SCIT treatment., Results: HDM AIT treatment ameliorated clinical symptoms while concurrently improved lung function parameters, such as FEV 1 /FVC, FEF 75 , FEF 50 and MMEF (p < .05). It is worth noting that FEF 75 values showed a highly significant, gradual and persistent increase (from 49.55 ± 1.27% at baseline to 71.89 ± 2.64% after 1 year of therapy) and 22 of 35 patients no longer had SAD after 1 year of treatment. BAT results revealed that AIT treatment significantly reduced basophil activity to the inhalant allergen mixtures containing HDM in vitro challenge from baseline. GO term and KEGG pathway enrichment analysis of basophils revealed that downregulated genes were mainly involved in immune cell activation, antigen presentation, and Th2 cell differentiation., Conclusions: Our study demonstrated that HDM AIT not only improved SAD related lung function parameters, but also reduced basophil activity. RNA sequencing revealed the inhibition of phagocytosis and the phagosome pathway in basophils which may affect the polarization of Th2 cell differentiation after HDM AIT., (© 2024 Wiley Periodicals LLC.)

Background: Locally advanced rectal cancer (LARC) presents significant treatment challenges, particularly as patient age may influence disease progression and treatment response. Understanding the differences in progression patterns and treatment outcomes between older patient (OP) and non-older patient (NOP) is essential for tailoring effective management strategies., Objectives: We aimed to explore the differences of progression pattern, postoperative treatment, and survival outcome between OP and NOP groups in LARC., Design/methods: The random survival forest model was used to determine the probability of time-to-event occurrence every 3 months. Patients in the NOP and OP group were both categorized into three risk groups based on progression-free survival nomogram scores. We employed inverse probability of treatment weighting (IPTW) analysis and the Surveillance, Epidemiology, and End Results (SEER) database to verify our findings., Results: Our results revealed that Groups 1, 2, and 3 experienced peaks in progression within the first 24 months in NOP group. As for OP group, Group 4 reached a progression peak at the 18th month, Group 5 at the 12th month, and Group 6 at the 9th month. In NOP group, high-risk patients who underwent postoperative chemotherapy had significantly improved overall survival compared to those who did not. Additionally, postoperative chemotherapy did not significantly improve prognosis for patients in low-, moderate-, or high-risk groups of OP group. Finally, the validation results of IPTW analysis and SEER database showed compliance with our findings., Conclusion: For NOP group, we recommended close follow-up during the first 2 years. As for OP group, it was suggested to conduct close follow-up at the 18th, 12th, and 9th month for low-, moderate-, and high-risk groups, respectively. Furthermore, postoperative chemotherapy can provide survival benefits for patients in high-risk group of NOP group. However, OP group patients should be informed that the potential benefits of postoperative chemotherapy may be minimal., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2024.)

The alarming escalation in cancer incidence and mortality has thrust into spotlight the quest for groundbreaking therapeutic strategies. Our research delves into the potential of RDIR780, a novel class of biomimetic nanoparticles cloaked in red blood cell membranes, to significantly enhance their in vivo persistence and therapeutic potency. Through an exhaustive suite of experiments, we have charted the therapeutic horizons of RDIR780 in the realms of tumor photothermal synergistic immunotherapy and targeted drug delivery. Preliminary in vitro cellular assays have revealed that RDIR780 not only achieves remarkable uptake by tumor cells but also triggers swift tumor cell death under the influence of laser irradiation. Subsequent in vivo fluorescence imaging studies have corroborated the nanoparticles' propensity for tumor-specific accumulation, thereby bolstering the case for precision medicine. The results of the precise imaging techniques of therapeutic trials conducted on mice with implanted tumors have underscored the profound impact of RDIR780 when synergized with an anti-PD-L1 antibody. This synergistic approach has shown to fairly eradicate tumor growth, marking a significant stride in the battle against cancer. This pioneering endeavor not only lays down a formidable groundwork for the evolution of long-circulating photothermal therapeutic nanoparticles but also heralds a new era of transformative clinical interventions., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (This journal is © The Royal Society of Chemistry.)

Previous studies have suggested that impaired spiral artery remodeling, placental dysfunction, and insufficient trophoblast infiltration are the etiology and pathogenesis of Preeclampsia (PE). Ring 1 and YY1 binding protein (RYBP) has been reported to be associated with trophoblast dysfunction. However, the molecular mechanism of RYBP involved in trophoblasts in the pathogenesis of PE is poorly defined. RYBP and Ubiquitin-specific peptidase 4 (USP4) mRNA levels were determined using real-time quantitative polymerase chain reaction (RT-qPCR). RYBP, USP4, p-PI3K, PI3K, p-AKT, and AKT protein levels were measured using western blot assay. Cell viability, proliferation, apoptosis, invasion, and migration were assessed using 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT), 5-ethynyl-2'-deoxyuridine (EdU), flow cytometry, transwell, and wound healing assays. After ubibrowser database analysis, the interaction between USP4 and RYBP was verified using Co-immunoprecipitation (CoIP) assay. RYBP and USP4 expression were upregulated in placental tissues from PE patients. By using JEG-3 and HTR-8/SVneo trophoblast cells, RYBP overexpression or USP4 upregulation could hinder cell viability, proliferation, invasion, migration, and promote apoptosis. Mechanistically, USP4 could trigger the deubiquitination of RYBP and prevent its degradation. In addition, USP4 repressed the PI3K/AKT signaling pathway by regulating RYBP. In total, Decreased USP4-mediated ubiquitination results in an adverse impact on trophoblast function by enhancing RYBP expression, providing a novel therapeutic target for PE., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

This study aimed to improve the traceability of rice-producing areas to address the increasing demand for accurate methods to confirm food quality and safety. Compound-specific δ 13 C of fatty acids, δ 13 C of starch and bulk of rice were measured. PCA, PLS-DA and VIP value analysis of the obtained data were performed to track the source of rice from the six regions. The PLS-DA model established with bulk δ 13 C, starch δ 13 C, and fatty acid δ 13 C, which clearly separated the rice from six regions. The VIP graph showed the value of starch, C18:0 and C18:2 δ 13 C values (VIP > 1) were important to distinguish the origin of rice. Also, according to loading plots the contribution of starch δ 13 C was the largest. The findings indicate that the introduction of starch δ 13 C improves the precision of rice traceability and provides an effective method for identifying rice origin., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Liu Yu has patent pending to Dalian Maritime University., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background and Hypothesis: Sensory gating deficit is considered a pathophysiological feature of schizophrenia, which has been linked to N-methyl-d-aspartate receptor (NMDAR) hypofunction as one of the potential underlying mechanisms. Here, we hypothesize that higher levels of NMDAR antibody (Ab) may contribute to the sensory gating deficits in schizophrenia., Study Design: We enrolled 72 non-smoking inpatients with first-episode schizophrenia (FES), most of them with only a relatively short duration of exposure to antipsychotic medications, and 51 non-smoking healthy controls (HC). Sensory gating was measured by P50 evoked potentials ratio and the difference between the two stimuli in an auditory paired-stimuli paradigm and serum NMDAR Ab levels were quantified by enzyme-linked immunosorbent assay., Study Results: The FES group showed higher serum NMDAR Ab levels [(9.23 ± 4.15) ng/mL vs. (7.08 ± 2.83) ng/mL; P = .002], higher P50 ratio (P = .002), and less P50 difference (P = .001) than HC. In partial correlation analysis, serum NMDAR Ab levels were positively correlated with the P50 ratio (r = 0.36, P = .003) and negatively with the P50 difference (r = -0.39, P = .001) in the FES group. The NMDAR Ab levels mediated the diagnosis of schizophrenia and P50 sensory gating deficits (P50 ratio and P50 difference)., Conclusions: Autoimmunity targeting NMDAR is a crucial intermediate mechanism in impaired sensory gating in patients with schizophrenia. The findings support early intervention targeting NMDAR for patients with schizophrenia., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

In recent years, digital dentistry has increasingly utilized advanced image analysis techniques, such as image classification and disease diagnosis, to improve clinical outcomes. Despite these advances, the lack of comprehensive benchmark datasets is a significant barrier. To address this gap, our research team develop LMCD-OR, a substantial collection of oral radiograph images designed to support extensive artificial intelligence (AI)-driven diagnostics. LMCD-OR comprises 3,818 digital imaging and communications in medicine (DICOM) oral X-ray images from local medical institutions that are meticulously annotated to provide broad category information for both primary dental outpatient services and detailed secondary disease diagnoses. This dataset is engineered to train and validate multiclassification models to improve the precision and scope of oral disease diagnostics. To ensure robust dataset validation, we employ four cutting-edge visual neural network classification models as benchmarks. These models are tested against rigorous performance metrics, demonstrating the ability of the dataset to support advanced image classification and disease diagnosis tasks. LMCD-OR is publicly available at http://dentaldataset.zeroacademy.net ., (© 2024. The Author(s).)

Although previous research has suggested that parenting style affects children's peer relationships, the influential mechanism remains a subject of debate. We propose that parental mentalizing plays a crucial role in parenting style and peer relationships. Therefore, this study aimed to explore the relationships between family parenting styles, parental mentalizing, and peer relationships during early adolescence. In this study, 379 primary school students (Mean age = 12.17 years, SD = 0.92) and their parents were assessed using the Family Parenting Style Scale, Peer Relationship Satisfaction Scale, and a distorted mentalizing task. The results showed a mediating effect of parental mentalizing between parenting style and peer relationships. For fathers, a favorable parenting style affects children's peer relationships through mentalizing. Among mothers, interference, protection, and punishment affect their children's peer relationships through mentalizing. In conclusion, parenting style affects peer relationships through parental mentalizing. Fathers'/mothers' parenting style and parental mentalizing affect their children's peer relationships differently.

Immunohistochemistry (IHC) is a widely used technique in diagnostic pathology and biomedical research, but there is still a need to shorten the operation process and reduce the cost of antibodies. This study aims to assess a novel IHC technique that incorporates mechanical microvibration (MMV) to expedite the process, reduce antibody consumption, and enhance staining quality. MMV was generated using coin vibration motors attached to glass slides mounted with consecutive tissue sections. Multiple antibodies targeting various antigens were used to stain cancerous and normal tissues, with and without microvibration. Various parameters were tested, including incubation durations, temperatures, and antibody dilutions. The novel method showed the potential to achieve comparable or superior outcomes in significantly less time, utilizing over 10 times less antibody than controls. MMV improved specific staining quality, yielding stronger, and better-defined positive reactions. This was validated through a multicenter double-blind assessment and quantitative image analysis. The possible mechanisms were also investigated. MMV shortens immunohistochemical staining duration, reduces antibody usage, and enhances staining specificity, likely by accelerating antibody movement and diffusion. These improvements translate to time and cost savings, offering clinical and financial value for diagnostic pathology and biomedical research., (© 2024 The Author(s). Engineering in Life Sciences published by Wiley‐VCH GmbH.)